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Sample records for decreases cerebral amyloid

  1. Cerebral amyloid angiopathy

    MedlinePlus

    Cerebral amyloid angiopathy is a neurological condition in which proteins called amyloid build up on the walls of the arteries ... The cause of cerebral amyloid angiopathy is unknown. Sometimes, it ... Persons with this condition have deposits of amyloid protein ...

  2. Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy

    PubMed Central

    Switzer, Aaron R.; McCreary, Cheryl; Batool, Saima; Stafford, Randall B.; Frayne, Richard; Goodyear, Bradley G.; Smith, Eric E.

    2016-01-01

    Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p < 0.001). White matter hyperintensity (WMH) volumes and number of cerebral microbleeds, both presumed to reflect CAA-mediated vascular injury, increased over time in CAA (p = 0.007 and p = 0.001, respectively). Longitudinal increases in WMH (rs = 0.04, p = 0.86) or cerebral microbleeds (rs = − 0.18, p = 0.45) were not associated with the longitudinal decrease in BOLD amplitudes. PMID:27104140

  3. Cerebral amyloid angiopathy

    MedlinePlus

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  4. Cerebral Amyloid Angiopathy: Emerging Concepts

    PubMed Central

    2015-01-01

    Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2* imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis

  5. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    MedlinePlus

    ... recurrent seizures (epilepsy). People with the Flemish and Italian types of hereditary cerebral amyloid angiopathy are prone ... amyloid angiopathy . APP gene mutations cause the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont types of this ...

  6. Amyloid angiopathy and lobar cerebral haemorrhage.

    PubMed Central

    Ishii, N; Nishihara, Y; Horie, A

    1984-01-01

    Seven cases of lobar cerebral haemorrhage due to amyloid angiopathy were found among 60 necropsy cases of intracerebral haemorrhage. Clinically five patients were demented and two had hypertension. Immediately after the onset of stroke there was a high incidence of headache and vomiting, followed by nuchal rigidity. Amyloid angiopathy was most prominent in the cerebral cortex and the leptomeninges. Senile plaques were noted in all cases. One should suspect that a haemorrhage may be due to amyloid angiopathy, when lobar cerebral haemorrhage occurs in an aged, normotensive patient with or without dementia. Surgical evacuation of the haematoma is inadvisable, because of the diffuse nature of amyloid angiopathy, high recurrence rate and less tendency to cause brain stem compression. Images PMID:6502178

  7. Neuropsychological Effects of Cerebral Amyloid Angiopathy.

    PubMed

    Schrag, Matthew; Kirshner, Howard

    2016-08-01

    Cerebral amyloid angiopathy is a condition of the cerebral arterioles and to a lesser extent capillaries and veins, wherein beta-amyloid is deposited. In arterioles, this preferentially targets vascular smooth muscle cells and in the later stages undermines the stability of the vessel. This condition is frequently comorbid with Alzheimer's disease and its role in cognitive impairment and dementia is a topic of considerable recent research. This article reviews recent literature which confirms that CAA independently contributes to cognitive impairment by potentiating the neurodegeneration of Alzheimer's disease, by predisposing to microhemorrhagic and microischemic injury to the brain parenchyma, and by interfering with the autoregulation of CNS blood flow. In this review, we discuss the clinical presentation of cerebral amyloid angiopathy, with a focus on the neuropsychological manifestations of this vasculopathy. PMID:27357378

  8. Alzheimer's silent partner: cerebral amyloid angiopathy.

    PubMed

    Cupino, Tanya L; Zabel, Matthew K

    2014-06-01

    Alzheimer's disease (AD) is the most common form of dementia, which completely lacks a viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. CAA manifests with deposition amyloid-beta (Aβ) within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it has demonstrated toxicity at super-physiological levels in vitro, Aβ load does not necessarily correlate with cognitive demise in humans. In this review, we describe the contributions of CAA to AD pathophysiology and important pathomechanisms that may lead to vascular fragility and hemorrhages. Additionally, we discuss the effect of Aβ on smooth muscle cell phenotype and viability, especially in terms of the complement cascade. PMID:24323728

  9. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity.

    PubMed

    Bales, Kelly R; O'Neill, Sharon M; Pozdnyakov, Nikolay; Pan, Feng; Caouette, David; Pi, YeQing; Wood, Kathleen M; Volfson, Dmitri; Cirrito, John R; Han, Byung-Hee; Johnson, Andrew W; Zipfel, Gregory J; Samad, Tarek A

    2016-02-01

    Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function. PMID:26493635

  10. Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications.

    PubMed

    Boulouis, Gregoire; Charidimou, Andreas; Greenberg, Steven M

    2016-06-01

    Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-β peptide (Aβ) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-β deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. PMID:27214698

  11. Impaired fasting glucose is associated with increased regional cerebral amyloid.

    PubMed

    Morris, Jill K; Vidoni, Eric D; Wilkins, Heather M; Archer, Ashley E; Burns, Nicole C; Karcher, Rainer T; Graves, Rasinio S; Swerdlow, Russell H; Thyfault, John P; Burns, Jeffrey M

    2016-08-01

    The Alzheimer's disease risk gene apolipoprotein E epsilon 4 (APOE ε4) is associated with increased cerebral amyloid. Although impaired glucose metabolism is linked to Alzheimer's disease risk, the relationship between impaired glycemia and cerebral amyloid is unclear. To investigate the independent effects of APOE ε4 and impaired glycemia on cerebral amyloid, we stratified nondemented subjects (n = 73) into 4 groups: normal glucose, APOE ε4 noncarrier (control [CNT]; n = 31), normal glucose, APOE ε4 carrier (E4 only; n = 14) impaired glycemia, APOE ε4 noncarrier (IG only; n = 18), and impaired glycemia, APOE ε4 carrier (IG+E4; n = 10). Cerebral amyloid differed both globally (p = 0.023) and regionally; precuneus (p = 0.007), posterior cingulate (PCC; p = 0.020), superior parietal cortex (SPC; p = 0.029), anterior cingulate (p = 0.027), and frontal cortex (p = 0.018). Post hoc analyses revealed that E4 only subjects had increased cerebral amyloid versus CNT globally and regionally in the precuneus, PCC, SPC, anterior cingulate, and frontal cortex. In IG only subjects, increased cerebral amyloid compared with CNT was restricted to precuneus, PCC, and SPC. IG+E4 subjects exhibited higher cerebral amyloid only in the precuneus relative to CNT. These results indicate that impaired glycemia and APOE ε4 genotype are independent risk factors for regional cerebral amyloid deposition. However, APOE ε4 and impaired glycemia did not have an additive effect on cerebral amyloid. PMID:27318141

  12. Longitudinal cerebral blood flow and amyloid deposition: an emerging pattern?

    PubMed Central

    Sojkova, Jitka; Beason-Held, Lori; Zhou, Yun; An, Yang; Kraut, Michael A; Ye, Weigo; Ferrucci, Luigi; Mathis, Chester A; Klunk, William E; Wong, Dean F; Resnick, Susan M

    2008-01-01

    Although cerebral amyloid deposition may precede cognitive impairment by decades, the relationship between amyloid deposition and longitudinal change in neuronal function has not been studied. The aim of this paper is to determine whether nondemented individuals with high and low amyloid burden show different patterns of longitudinal regional cerebral blood flow (rCBF) changes in the years preceding measurement of amyloid deposition. Methods Twenty-eight nondemented participants (mean (SD) age at [11C] PIB 82.5(4.8) yrs; 6 mildly impaired) from the Baltimore Longitudinal Study of Aging underwent yearly resting-state [15O]H2O PET scans for up to 8 years. [11C]PIB images of amyloid deposition were acquired on average 10.8(0.8) years after the first CBF scan. [11C]PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves. Based on mean cortical DVR, participants were divided into high and low [11C]PIB retention groups. Differences in longitudinal rCBF changes between high and low [11C]PIB groups were investigated by voxel-based analysis. Results Longitudinal rCBF changes differed significantly between high (n=10) and low (n=18) [11C]PIB groups (p<=0.001). Greater longitudinal decreases in rCBF in the high [11C]PIB group were seen in right anterior/mid cingulate, right supramarginal gyrus, left thalamus and midbrain bilaterally relative to the low group. Greater increases in rCBF over time in the high [11C]PIB group were found in left medial and inferior frontal gyri, right precuneus, left inferior parietal lobule, and the left postcentral gyrus. Conclusion In this group of nondemented older adults, those with high [11C]PIB show greater longitudinal declines in rCBF in certain areas, representing regions with greater decrements in neuronal function. Greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent an attempt to preserve

  13. Magnetic Fluids Have Ability to Decrease Amyloid Aggregation Associated with Amyloid-Related Diseases

    NASA Astrophysics Data System (ADS)

    Antosova, Andrea; Koneracka, Martina; Siposova, Katarina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fabian, Martin; Kopcansky, Peter; Gazova, Zuzana

    2010-12-01

    At least twenty human proteins can fold abnormally to form pathological deposits that are associated with several amyloid-related diseases. We have investigated the effect of four magnetic fluids (MFs)—electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate (MF2, MF3 and MF4) with adsorbed BSA (MF2) or dextran (MF4)—on amyloid aggregation of two proteins, human insulin and chicken egg lysozyme. The morphology, particle size and size distribution of the prepared magnetic fluids were characterized. We have found that MFs are able to decrease amyloid aggregation of both studied proteins and the extent of depolymerization depended on the MF properties. The most effective reduction was observed for MF4 as 90% decrease of amyloids was detected for insulin and lysozyme amyloid aggregates. Our findings indicate that MFs have potential to be used for treatment of amyloid diseases.

  14. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy.

    PubMed

    Reijmer, Yael D; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert-Jan; Rosand, Jonathan; Johnson, Keith A; Viswanathan, Anand; Gurol, M Edip; Greenberg, Steven M

    2015-01-01

    Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging

  15. [Sporadic Cerebral Amyloid Angiopathy: An Overview with Clinical Cases].

    PubMed

    Schöberl, F; Eren, O E; Wollenweber, F A; Kraus, T; Kellert, L

    2016-09-01

    Sporadic cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in the elderly. Neuropathologically, it is characterized by deposition of amyloid-ß (Aß) in the wall of small to medium-sized arteries, capillaries and venules of the cerebral cortex and leptomeninges. Over the last years it was recognized as an important cause of spontaneous intracerebral hemorrhage and cognitive deficits in the elderly. The clinical and radiological manifestations are diverse ranging from acute onset focal neurological deficits due to intracerebral lobar hemorrhage to subacute progressive cognitive impairment due to Aß-mediated inflammation confluent subcortical edema. The wide clinico-radiological spectrum of CAA is a major challenge for the neurologist and stroke physician. This review provides a structured and detailed look at recent developments in CAA, and is illustrated with case studies. PMID:27607067

  16. Cerebral amyloid angiopathy-related inflammation: an emerging disease.

    PubMed

    Savoiardo, M; Erbetta, A; Di Francesco, J C; Brioschi, M; Silani, V; Falini, A; Storchi, G; Brighina, L; Ferrarese, C; Ticozzi, N; Messina, S; Girotti, F

    2011-05-15

    Three elderly patients with, respectively: mild cognitive impairment, severe and progressive neurologic involvement, and focal neurologic deficit, were observed. MRI showed multiple areas of white matter edema, at times partially involving the cortex, in the first two patients, and a single area in the third. Treatment with steroids determined the disappearance of the lesions and clinical amelioration. The key to the diagnosis of cerebral amyloid angiopathy-related inflammation (CAA-ri) was the demonstration, with appropriate MRI sequences, of microbleeds consistent with cerebral amyloid angiopathy (CAA). This diagnosis was supported by genetic analysis of APOE with demonstration of ε4/ε4 genotype, found in about 80% of CAA patients who develop inflammatory changes. In the appropriate clinical setting, MRI demonstration of microbleeds supported by results of genetic analysis of APOE may strongly support the diagnosis of CAA-ri thus avoiding cerebral biopsy. PMID:24059616

  17. Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.

    PubMed

    van Veluw, Susanne J; Biessels, Geert Jan; Bouvy, Willem H; Spliet, Wim Gm; Zwanenburg, Jaco Jm; Luijten, Peter R; Macklin, Eric A; Rozemuller, Annemieke Jm; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand; Martinez-Ramirez, Sergi

    2016-03-01

    Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3-7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity. PMID:26661250

  18. Imaging linear birefringence and dichroism in cerebral amyloid pathologies

    PubMed Central

    Jin, Lee-Way; Claborn, Kacey A.; Kurimoto, Miki; Geday, Morten A.; Maezawa, Izumi; Sohraby, Faranak; Estrada, Marcus; Kaminksy, Werner; Kahr, Bart

    2003-01-01

    New advances in polarized light microscopy were used to image Congo red-stained cerebral amyloidosis in sharp relief. The rotating-polarizer method was used to separate the optical effects of transmission, linear birefringence, extinction, linear dichroism, and orientation of the electric dipole transition moments and to display them as false-color maps. These effects are typically convolved in an ordinary polarized light microscope. In this way, we show that the amyloid deposits in Alzheimer's disease plaques contain structurally disordered centers, providing clues to mechanisms of crystallization of amyloid in vivo. Comparisons are made with plaques from tissues of subjects having Down's syndrome and a prion disease. In plaques characteristic of each disease, the Congo red molecules are oriented radially. The optical orientation in amyloid deposited in blood vessels from subjects having cerebral amyloid angiopathy was 90° out of phase from that in the plaques, suggesting that the fibrils run tangentially with respect to the circumference of the blood vessels. Our result supports an early model in which Congo red molecules are aligned along the long fiber axis and is in contrast to the most recent binding models that are based on computation. This investigation illustrates that the latest methods for the optical analysis of heterogeneous substances are useful for in situ study of amyloid. PMID:14668440

  19. The Cerebrovascular Basement Membrane: Role in the Clearance of β-amyloid and Cerebral Amyloid Angiopathy

    PubMed Central

    Morris, Alan W. J.; Carare, Roxana O.; Schreiber, Stefanie; Hawkes, Cheryl A.

    2014-01-01

    Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer’s disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA. PMID:25285078

  20. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia

    PubMed Central

    Jansen, Willemijn J.; Ossenkoppele, Rik; Knol, Dirk L.; Tijms, Betty M.; Scheltens, Philip; Verhey, Frans R. J.; Visser, Pieter Jelle

    2015-01-01

    IMPORTANCE Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOEε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and

  1. Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch Type

    NASA Astrophysics Data System (ADS)

    Levy, Efrat; Carman, Mark D.; Fernandez-Madrid, Ivan J.; Power, Michael D.; Lieberburg, Ivan; van Duinen, Sjoerd G.; Bots, Gerard Th. A. M.; Luyendijk, Willem; Frangione, Blas

    1990-06-01

    An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

  2. Labeling of cerebral amyloid in vivo with a monoclonal antibody.

    PubMed

    Walker, L C; Price, D L; Voytko, M L; Schenk, D B

    1994-07-01

    We assessed the ability of a murine monoclonal antibody to bind selectively to beta-amyloid in the brains of living nonhuman primates. To circumvent the blood-brain barrier, we injected unlabeled antibody 10D5 (murine whole IgG1 and/or Fab fragments) into the cerebrospinal fluid of the cisterna magna in three aged monkeys. A control animal was given an intracisternal injection of nonimmune mouse whole IgG plus Fab. Twenty-four hours later, the animals were perfused and prepared for immunohistochemical detection of bound murine immunoglobulin in brain. All three experimental animals showed selective binding of 10D5 to approximately 5-15% of amyloid deposits in cerebral cortex, primarily near the cortical surface. There was no labeling in the control animal. In vivo-labeled deposits were confirmed to be beta-amyloid by electron microscopy and by in vitro immunohistochemistry in adjacent sections. The animals tolerated the injection well, although some polymorphonuclear leukocytes infiltrated portions of the subarachnoid space and superficial neocortex. These results provide the first demonstration that it may be feasible to selectively direct a tagged monoclonal antibody to beta-amyloid in the brain for therapeutic or diagnostic purposes. With enhancement of labeling efficiency, the method also may be useful for studying the progression of beta-amyloidosis in experimental animals using emission tomography. PMID:8021711

  3. Cerebral Amyloid Angiopathy: A Hidden Risk for IV Thrombolysis?

    PubMed Central

    Felling, Ryan J.; Faigle, Roland; Ho, Cheng-Ying; Llinas, Rafael H.; Urrutia, Victor C.

    2015-01-01

    Recombinant tissue plasminogen activator (t-PA) is the only FDA approved therapy for acute ischemic stroke. Cerebral microbleeds (CMBs) or cerebral amyloid angiopathy (CAA) are currently not contraindications, however, data regarding this complex issue are limited. We report 2 cases of fatal intracerebral hemorrhage (sICH) after IV t-PA, each with evidence of CAA. Patients with CAA may have increased risk for IV thrombolysis-associated sICH. We highlight the severe and catastrophic pattern of ICH, which may be a defining characteristic, and discuss the limitations of our current understanding of the risk of thrombolysis-associated ICH in patients with CAA and/or CMBs. PMID:26280025

  4. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.

    PubMed

    Jaunmuktane, Zane; Mead, Simon; Ellis, Matthew; Wadsworth, Jonathan D F; Nicoll, Andrew J; Kenny, Joanna; Launchbury, Francesca; Linehan, Jacqueline; Richard-Loendt, Angela; Walker, A Sarah; Rudge, Peter; Collinge, John; Brandner, Sebastian

    2015-09-10

    More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer's disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aβ and other proteopathic

  5. The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases.

    PubMed

    Mendel, T A; Wierzba-Bobrowicz, T; Lewandowska, E; Stępień, T; Szpak, G M

    2013-12-01

    The process of β-amyloid accumulation in cerebral vessels is presented. Cerebral amyloid angiopathy (CAA) was confirmed during an autopsy. It was diagnosed according to the Boston criteria. Cerebral amyloid angiopathy can involve all kinds of cerebral vessels (cortical and leptomeningeal arterioles, capillaries and veins). The development of CAA is a progressive process. β-amyloid appears first in the tunica media, surrounding smooth muscle cells, and in the adventitia. β-amyloid is progressively accumulated, causing a gradual loss of smooth muscle cells in the vessel wall and finally replacing them. Then, the detachment and delamination of the outer part of the tunica media results in the "double barrel" appearance, fibrinoid necrosis, and microaneurysm formation. Microbleeding with perivascular deposition of erythrocytes and blood breakdown products can also occur. β-amyloid can also be deposited in the surrounding of the affected vessels of the brain parenchyma, known as "dysphoric CAA". Ultrastructurally, when deposits of amyloid fibers were localized in or outside the arteriolar wall, the degenerating vascular smooth muscle cells were observed. In the Institute of Psychiatry and Neurology the study was carried out in a group of 48 patients who died due to intracerebral hemorrhage caused by sporadic CAA. PMID:24375040

  6. Dementia in cerebral amyloid angiopathy: a clinicopathological study.

    PubMed

    Yoshimura, M; Yamanouchi, H; Kuzuhara, S; Mori, H; Sugiura, S; Mizutani, T; Shimada, H; Tomonaga, M; Toyokura, Y

    1992-10-01

    Dementia is in addition to cerebral haemorrhage major symptom of cerebral amyloid angiopathy (CAa). In order to explore the pathological basis for dementia in CAa-related conditions, we made a clinicopathological analysis of CAa, with special attention to dementia. Among 150 patients (mean age 78.6 years) with autopsy-proven intracranial haemorrhage in Tokyo Metropolitan Geriatric Medical Center, CAa with cerebral haemorrhage accounted for 8.0% (12 cases), associated with hypertension and metastatic brain tumour. Among 38 patients with lobar haemorrhage, CAa represented the second most common cause (21.1%) of intracranial haemorrhage after hypertension. A total of 20 patients with CAa (mean age 82.5 years) were studies clinically and pathologically. Hypertension was present in 50%. Thirteen had a history of stroke and others had either ill-defined or no strokes. The average number of strokes 2.9. Fifteen patients (75%) had dementia. Based on the clinicopathological grounds for dementia, CAa-related conditions could be divided into three subtypes: "haemorrhagic", "dementia-haemorrhagic" and "dementia" type. Haemorrhagic type (30%, 6 cases) showed multiple recurrent lobar haemorrhages caused by CAa. Hypertension was present in only 1 patient. The incidence of senile plaques and neurofibrillary tangles was generally correlated with age. Only 1 patient had dementia. The dementia-haemorrhagic type (40%, 8 patients) had recurrent strokes with cerebral haemorrhage after preceding dementia. There were two different neuropathological subsets: CAa with atypical senile dementia of Alzheimer type (SDAT) and CAa with diffuse leucoencephalopathy. Patients with CAa with atypical SDAT had multiple cerebral haemorrhages caused by CAa combined with atypical Alzheimer-type pathology. Patients with CAa with diffuse leucoencephalopathy had cerebral haemorrhages in combination with diffuse white matter damage like Binswanger's subcortical vascular encephalopathy (BSVE). The incidence of

  7. Multiple medullary venous malformations decreasing cerebral blood flow: Case report

    SciTech Connect

    Tomura, N.; Inugami, A.; Uemura, K.; Hadeishi, H.; Yasui, N. )

    1991-02-01

    A rare case of multiple medullary venous malformations in the right cerebral hemisphere is reported. The literature review yielded only one case of multiple medullary venous malformations. Computed tomography scan showed multiple calcified lesions with linear contrast enhancement representing abnormal dilated vessels and mild atrophic change of the right cerebral hemisphere. Single-photon emission computed tomography using N-isopropyl-p-({sup 123}I) iodoamphetamine demonstrated decreased cerebral blood flow in the right cerebral hemisphere.

  8. Outcome Markers for Clinical Trials in Cerebral Amyloid Angiopathy

    PubMed Central

    Greenberg, Steven M.; Rustam Al-Shahi, Salman; Biessels, Geert Jan; van Buchem, Mark; Cordonnier, Charlotte; Lee, Jin-Moo; Montaner, Joan; Schneider, Julie A.; Smith, Eric E; Vernooij, Meike; Werring, David J.

    2014-01-01

    Efforts are underway for early-phase trials of candidate therapies for cerebral amyloid angiopathy (CAA), an untreatable cause of hemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the lack of consensus on measuring treatment effectiveness. We review a range of potential outcome markers for CAA against the ideal criteria of being clinically meaningful, closely reflective of biological progression, efficient for smaller/shorter trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but relatively low statistical efficiency and thus more applicability for later phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient outcomes are those that are potentially reversible with treatment, though their clinical significance remains unproven. Many of the candidate outcomes for CAA trials are likely to be applicable to other small vessel brain diseases as well. Considerations emerging from this review outline a path towards rapid and efficient testing of emerging candidate therapies for CAA and other small vessel diseases. PMID:24581702

  9. Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid β proteins in amyloid precursor protein transgenic mice.

    PubMed

    Fujiwara, H; Takayama, S; Iwasaki, K; Tabuchi, M; Yamaguchi, T; Sekiguchi, K; Ikarashi, Y; Kudo, Y; Kase, Y; Arai, H; Yaegashi, N

    2011-04-28

    The deposition of amyloid β protein (Aβ) is a consistent pathological hallmark of Alzheimer's disease (AD) brains. Therefore, inhibition of Aβ aggregation in the brain is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. An in vitro study demonstrated that yokukansan (YKS), a traditional Japanese medicine, inhibited Aβ aggregation in a concentration-dependent manner. An in vivo study demonstrated that YKS and Uncaria hook (UH), a constituent of YKS, prevented the accumulation of cerebral Aβ. YKS also improved the memory disturbance and abnormal social interaction such as increased aggressive behavior and decreased social behavior in amyloid precursor protein transgenic mice. These results suggest that YKS is likely to be a potent and novel therapeutic agent to prevent and/or treat AD, and that this may be attributed to UH. PMID:21303686

  10. Sporadic cerebral amyloid angiopathy: An important cause of cerebral hemorrhage in the elderly.

    PubMed

    Bano, Shahina; Yadav, Sachchida Nand; Garga, Umesh Chandra; Chaudhary, Vikas

    2011-01-01

    Cerebral amyloid angiopathy (CAA) is an important cause of primary intracerebral hemorrhage (PICH) in the elderly. Although there are no pathognomic clinical features of CAA-related PICH, the association of white matter changes with lobar, recurrent, or multiple simultaneous hemorrhages in older patients should raise the suspicion of its diagnosis. A definitive diagnosis of CAA requires pathologic examination of the affected tissue. However, with modern imaging techniques, it is possible to diagnose the "probable CAA" in patients presenting with PICH. Gradient-echo magnetic resonance imaging is a very sensitive, noninvasive technique for identifying microhemorrhages in life. The diagnosis of CAA is important because of the likely implication it has on future management targeted to reduce risk of future bleeding. PMID:21716867

  11. Cerebral Amyloid and Hypertension are Independently Associated with White Matter Lesions in Elderly

    PubMed Central

    Scott, Julia A.; Braskie, Meredith N.; Tosun, Duygu; Thompson, Paul M.; Weiner, Michael; DeCarli, Charles; Carmichael, Owen T.

    2015-01-01

    In cognitively normal (CN) elderly individuals, white matter hyperintensities (WMH) are commonly viewed as a marker of cerebral small vessel disease (SVD). SVD is due to exposure to systemic vascular injury processes associated with highly prevalent vascular risk factors (VRFs) such as hypertension, high cholesterol, and diabetes. However, cerebral amyloid accumulation is also prevalent in this population and is associated with WMH accrual. Therefore, we examined the independent associations of amyloid burden and VRFs with WMH burden in CN elderly individuals with low to moderate vascular risk. Participants (n = 150) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) received fluid attenuated inversion recovery (FLAIR) MRI at study entry. Total WMH volume was calculated from FLAIR images co-registered with structural MRI. Amyloid burden was determined by cerebrospinal fluid Aβ1-42 levels. Clinical histories of VRFs, as well as current measurements of vascular status, were recorded during a baseline clinical evaluation. We tested ridge regression models for independent associations and interactions of elevated blood pressure (BP) and amyloid to total WMH volume. We found that greater amyloid burden and a clinical history of hypertension were independently associated with greater WMH volume. In addition, elevated BP modified the association between amyloid and WMH, such that those with either current or past evidence of elevated BP had greater WMH volumes at a given burden of amyloid. These findings are consistent with the hypothesis that cerebral amyloid accumulation and VRFs are independently associated with clinically latent white matter damage represented by WMHs. The potential contribution of amyloid to WMHs should be further explored, even among elderly individuals without cognitive impairment and with limited VRF exposure. PMID:26648866

  12. Amyloid-β peptide absence in short term effects on kinase activity of energy metabolism in mice hippocampus and cerebral cortex.

    PubMed

    Ianiski, Francine R; Rech, Virginia C; Nishihira, Vivian S K; Alves, Catiane B; Baldissera, Matheus D; Wilhelm, Ethel A; Luchese, Cristiane

    2016-07-11

    Considering that Alzheimer's disease is a prevalent neurodegenerative disease worldwide, we investigated the activities of three key kinases: creatine kinase, pyruvate kinase and adenylate kinase in the hippocampus and cerebral cortex in Alzheimer's disease model. Male adult Swiss mice received amyloid-β or saline. One day after, mice were treated with blank nanocapsules (17 ml/kg) or meloxicam-loaded nanocapsules (5 mg/kg) or free meloxicam (5 mg/kg). Treatments were performed on alternating days, until the end of the experimental protocol. In the fourteenth day, kinases activities were performed. Amyloid-β did not change the kinases activity in the hippocampus and cerebral cortex of mice. However, free meloxicam decrease the creatine kinase activity in mitochondrial-rich fraction in the group induced by amyloid-β, but for the cytosolic fraction, it has raised in the activity of pyruvate kinase activity in cerebral cortex. Further, meloxicam-loaded nanocapsules administration reduced adenylate kinase activity in the hippocampus of mice injected by amyloid-β. In conclusion we observed absence in short-term effects in kinases activities of energy metabolism in mice hippocampus and cerebral cortex using amyloid-β peptide model. These findings established the foundation to further study the kinases in phosphoryltransfer network changes observed in the brains of patients post-mortem with Alzheimer's disease. PMID:27411072

  13. Cerebral Amyloid Angiopathy and Parenchymal Amyloid Deposition in Transgenic Mice Expressing the Danish Mutant Form of Human BRI2

    PubMed Central

    Vidal, Ruben; Barbeito, Ana G; Miravalle, Leticia; Ghetti, Bernardino

    2009-01-01

    Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cataracts, hearing impairment, cerebellar ataxia and dementia. Neuropathologically, FDD is characterized by the presence of widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition and neurofibrillary tangles. FDD is caused by a 10-nucleotide duplication-insertion in the BRI2 gene that generates a larger-than-normal precursor protein, of which the Danish amyloid subunit (ADan) comprises the last 34 amino acids. Here, we describe a transgenic mouse model for FDD (Tg-FDD) in which the mouse Prnp (prion protein) promoter drives the expression of the Danish mutant form of human BRI2. The main neuropathological findings in Tg-FDD mice are the presence of widespread CAA and parenchymal deposition of ADan. In addition, we observe the presence of amyloid-associated gliosis, an inflammatory response and deposition of oligomeric ADan. As the animals aged, they showed abnormal grooming behavior, an arched back, and walked with a wide-based gait and shorter steps. This mouse model may give insights on the pathogenesis of FDD and will prove useful for the development of therapeutics. Moreover, the study of Tg-FDD mice may offer new insights into the role of amyloid in neurodegeneration in other disorders, including Alzheimer disease. PMID:18410407

  14. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

    PubMed

    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  15. Clinical Neuropathological Analysis of 10 Cases of Cerebral Amyloid Angiopathy-Related Cerebral Lobar Hemorrhage

    PubMed Central

    Su, Dong-Feng; Chen, Hui-Sheng; Fang, Qu

    2015-01-01

    Objective The clinical and pathological characteristics of 10 cases of cerebral amyloid angiopathy (CAA)-related cerebral lobar hemorrhage (CLH) that was diagnosed at autopsy were investigated to facilitate the diagnosis of this condition. Methods The clinical characteristics of 10 cases of CAA-related CLH were retrospectively reviewed, and a neuropathological examination was performed on autopsy samples. Results The 10 cases included two with a single lobar hemorrhage and eight with multifocal lobar hemorrhages. In all of the cases, the hemorrhage bled into the subarachnoid space. Pathological examinations of the 10 cases revealed microaneurysms in two, double barrel-like changes in four, multifocal arteriolar clusters in five, obliterative onion skin-like intimal changes in four, fibrinoid necrosis of the vessels in seven, neurofibrillary tangles in eight, and senile plaques in five cases. Conclusion CAA-related CLHs were located primarily in the parietal, temporal, and occipital lobes. These hemorrhages normally consisted of multiple repeated CLHs that frequently bled into the subarachnoid space. CAA-associated microvascular lesions may be the pathological factor underlying CLH. PMID:26279810

  16. Effect of Cerebral Amyloid Angiopathy on Brain Iron, Copper, and Zinc in Alzheimer’s Disease

    PubMed Central

    Schrag, Matthew; Crofton, Andrew; Zabel, Matthew; Jiffry, Arshad; Kirsch, David; Dickson, April; Mao, Xiao Wen; Vinters, Harry V.; Domaille, Dylan W.; Chang, Christopher J.; Kirsch, Wolff

    2015-01-01

    Cerebral amyloid angiopathy (CAA) is a vascular lesion associated with Alzheimer’s disease (AD) present in up to 95% of AD patients and produces MRI-detectable microbleeds in many of these patients. It is possible that CAA-related microbleeding is a source of pathological iron in the AD brain. Because the homeostasis of copper, iron, and zinc are so intimately linked, we determined whether CAA contributes to changes in the brain levels of these metals. We obtained brain tissue from AD patients with severe CAA to compare to AD patients without evidence of vascular amyloid-β. Patients with severe CAA had significantly higher non-heme iron levels. Histologically, iron was deposited in the walls of large CAA-affected vessels. Zinc levels were significantly elevated in grey matter in both the CAA and non-CAA AD tissue, but no vascular staining was noted in CAA cases. Copper levels were decreased in both CAA and non-CAA AD tissues and copper was found to be prominently deposited on the vasculature in CAA. Together, these findings demonstrate that CAA is a significant variable affecting transition metals in AD. PMID:21187585

  17. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  18. Imaging Findings of Cerebral Amyloid Angiopathy, Aβ-Related Angiitis (ABRA), and Cerebral Amyloid Angiopathy–Related Inflammation

    PubMed Central

    Salvarani, Carlo; Morris, Jonathan M.; Giannini, Caterina; Brown, Robert D.; Christianson, Teresa; Hunder, Gene G.

    2016-01-01

    Abstract Vascular inflammation is present in a subset of patients with cerebral amyloid angiopathy (CAA) and has a major influence in determining the disease manifestations. Radiological characterization of this subset is particularly important to achieve early recognition and treatment. We conducted this study to investigate the role of imaging in differentiating CAA with and without inflammation. We reviewed neuroimaging findings for 54 patients seen at Mayo Clinic over 25 years with pathological evidence of CAA and with available neuroimaging at the time of diagnosis. Clinical data were also recorded. Patients were grouped into CAA alone (no vascular inflammation), Aβ-related angiitis or ABRA (angiodestructive inflammation), and CAA-related inflammation or CAA-RI (perivascular inflammation). Imaging findings at presentation were compared among patient subgroups. Radiological features supporting a diagnosis of ABRA or CAA-RI were identified. Radiologic findings at diagnosis were available in 27 patients with CAA without inflammation, 22 with ABRA, and 5 with CAA-RI. On MRI, leptomeningeal disease alone or with infiltrative white matter was significantly more frequent at presentation in patients with ABRA or CAA-RI compared with those with CAA (29.6% vs. 3.7%, P = 0.02; and 40.7% vs. 3.7%, P = 0.002, respectively), whereas lobar hemorrhage was more frequent in patients with CAA (62.3% vs. 7.4%, P = 0.0001). Overall, leptomeningeal involvement at presentation was present in 70.4% of patients with ABRA or CAA-RI and in only 7.4% of patients with CAA (P = 0.0001). The sensitivity and specificity of leptomeningeal enhancement to identify patients with ABRA or CAA-RI were 70.4% and 92.6%, respectively, whereas the positive likelihood ratio (LR) was 9.5. The sensitivity and specificity of intracerebral hemorrhage to identify patients with CAA were 62.9% and 92.6%, respectively, whereas the positive LR was 8.5. Microbleeds were found in 70.4% of patients

  19. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy☆

    PubMed Central

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A.; Smyth, Neil R.; Smith, Colin; Salman, Rustam Al-Shahi; Samarasekera, Neshika; Nicoll, James A.R.; Attems, Johannes; Kalaria, Rajesh N.; Weller, Roy O.; Carare, Roxana O.

    2016-01-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327684

  20. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.

    PubMed

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A; Smyth, Neil R; Smith, Colin; Al-Shahi Salman, Rustam; Samarasekera, Neshika; Nicoll, James A R; Attems, Johannes; Kalaria, Rajesh N; Weller, Roy O; Carare, Roxana O

    2016-05-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327684

  1. Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions.

    PubMed

    Charidimou, Andreas; Linn, Jennifer; Vernooij, Meike W; Opherk, Christian; Akoudad, Saloua; Baron, Jean-Claude; Greenberg, Steven M; Jäger, Hans Rolf; Werring, David J

    2015-08-01

    Cortical superficial siderosis describes a distinct pattern of blood-breakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord. Although cortical superficial siderosis has many possible causes, it is emerging as a key feature of cerebral amyloid angiopathy, a common and important age-related cerebral small vessel disorder leading to intracerebral haemorrhage and dementia. In cerebral amyloid angiopathy cohorts, cortical superficial siderosis is associated with characteristic clinical symptoms, including transient focal neurological episodes; preliminary data also suggest an association with a high risk of future intracerebral haemorrhage, with potential implications for antithrombotic treatment decisions. Thus, cortical superficial siderosis is of relevance to neurologists working in neurovascular, memory and epilepsy clinics, and neurovascular emergency services, emphasizing the need for appropriate blood-sensitive magnetic resonance sequences to be routinely acquired in these clinical settings. In this review we focus on recent developments in neuroimaging and detection, aetiology, prevalence, pathophysiology and clinical significance of cortical superficial siderosis, with a particular emphasis on cerebral amyloid angiopathy. We also highlight important areas for future investigation and propose standards for evaluating cortical superficial siderosis in research studies. PMID:26115675

  2. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

    PubMed

    Merlini, Mario; Wanner, Debora; Nitsch, Roger M

    2016-05-01

    Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95 % CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95 % CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process

  3. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  4. The influence of the amyloid ß-protein and its precursor in modulating cerebral hemostasis.

    PubMed

    Van Nostrand, William E

    2016-05-01

    Ischemic and hemorrhagic strokes are a significant cause of brain injury leading to vascular cognitive impairment and dementia (VCID). These deleterious events largely result from disruption of cerebral hemostasis, a well-controlled and delicate balance between thrombotic and fibrinolytic pathways in cerebral blood vessels and surrounding brain tissue. Ischemia and hemorrhage are both commonly associated with cerebrovascular deposition of amyloid ß-protein (Aß). In this regard, Aß directly and indirectly modulates cerebral thrombosis and fibrinolysis. Further, major isoforms of the Aß precursor protein (AßPP) function as a potent inhibitor of pro-thrombotic proteinases. The purpose of this review article is to summarize recent research on how cerebral vascular Aß and AßPP influence cerebral hemostasis. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26519139

  5. Imaging of Cerebral Amyloid Angiopathy with Bivalent (99m)Tc-Hydroxamamide Complexes.

    PubMed

    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Matsumura, Kenji; Yoshimura, Masashi; Kimura, Hiroyuki; Ishibashi-Ueda, Hatsue; Okamoto, Yoko; Ihara, Masafumi; Saji, Hideo

    2016-01-01

    Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer's disease (AD). We previously reported (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1-42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1-40) aggregates deposited mainly in CAA and a brain uptake study were performed for (99m)Tc-Ham complexes, and all (99m)Tc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1-40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent (99m)Tc-Ham complexes ([(99m)Tc]SB2A and [(99m)Tc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the (99m)Tc-Ham complex. PMID:27181612

  6. Imaging of Cerebral Amyloid Angiopathy with Bivalent 99mTc-Hydroxamamide Complexes

    PubMed Central

    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Matsumura, Kenji; Yoshimura, Masashi; Kimura, Hiroyuki; Ishibashi-Ueda, Hatsue; Okamoto, Yoko; Ihara, Masafumi; Saji, Hideo

    2016-01-01

    Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer’s disease (AD). We previously reported 99mTc-hydroxamamide (99mTc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1–42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1–40) aggregates deposited mainly in CAA and a brain uptake study were performed for 99mTc-Ham complexes, and all 99mTc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1–40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent 99mTc-Ham complexes ([99mTc]SB2A and [99mTc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the 99mTc-Ham complex. PMID:27181612

  7. Imaging of Cerebral Amyloid Angiopathy with Bivalent 99mTc-Hydroxamamide Complexes

    NASA Astrophysics Data System (ADS)

    Iikuni, Shimpei; Ono, Masahiro; Watanabe, Hiroyuki; Matsumura, Kenji; Yoshimura, Masashi; Kimura, Hiroyuki; Ishibashi-Ueda, Hatsue; Okamoto, Yoko; Ihara, Masafumi; Saji, Hideo

    2016-05-01

    Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer’s disease (AD). We previously reported 99mTc-hydroxamamide (99mTc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1–42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1–40) aggregates deposited mainly in CAA and a brain uptake study were performed for 99mTc-Ham complexes, and all 99mTc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1–40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent 99mTc-Ham complexes ([99mTc]SB2A and [99mTc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the 99mTc-Ham complex.

  8. Cerebral Amyloid Angiopathy-Related Inflammation: Report of a Case with Very Difficult Therapeutic Management

    PubMed Central

    Crosta, Francesca; Orlandi, Berardino; De Santis, Federica; Passalacqua, Gianni; DiFrancesco, Jacopo C.; Piazza, Fabrizio; Catalucci, Alessia; Desideri, Giovambattista; Marini, Carmine

    2015-01-01

    Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri) results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF). Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis. PMID:26351601

  9. Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice*

    PubMed Central

    Lefterov, Iliya; Fitz, Nicholas F.; Cronican, Andrea A.; Fogg, Allison; Lefterov, Preslav; Kodali, Ravindra; Wetzel, Ronald; Koldamova, Radosveta

    2010-01-01

    A hallmark of Alzheimer disease (AD) is the deposition of amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ40 aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of Aβ42 and decreases Aβ42 toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1ΔE9 to apoA-IKO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1ΔE9 mice. Further characterization of APP/PS1ΔE9/apoA-IKO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Aβ oligomer levels, Aβ plaque load, or levels of insoluble Aβ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Aβ isolated from cerebral blood vessels. Our data show that in APP/PS1ΔE9/apoA-IKO mice, insoluble Aβ40 is increased more than 10-fold, and Aβ42 is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1ΔE9/apoA-IKO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Aβ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1ΔE9 mice in parallel to significantly increased cerebral amyloid angiopathy. PMID:20739292

  10. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography

    PubMed Central

    Mattsson, Niklas

    2016-01-01

    See Rabinovici (doi:10.1093/brain/aww025) for a scientific commentary on this article. Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer’s disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer’s disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. All underwent 18F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1–4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer’s disease dementia. The results were replicated after

  11. Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

    PubMed

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-05-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involvement of CAA in microbleed formation. Here, we show in a Tg2576 mouse model of Alzheimer's disease, that the combination of histochemical staining and an optical clearing method called optical histology, enables simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microbleeds, and amyloid deposits. Our data suggest that microbleeds are localized within the brain regions affected by vascular amyloid deposits. All observed microhemorrhages (n=39) were in close proximity (0 to 144μm) with vessels affected by CAA. Our data suggest that the predominant type of CAA-related microbleed is associated with leaky or ruptured hemorrhagic microvasculature. The proposed methodological and instrumental approach will allow future study of the relationship between CAA and microbleeds during disease development and in response to treatment strategies. PMID:26876114

  12. Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice.

    PubMed

    Han, Byung Hee; Zhou, Meng-Liang; Johnson, Andrew W; Singh, Itender; Liao, Fan; Vellimana, Ananth K; Nelson, James W; Milner, Eric; Cirrito, John R; Basak, Jacob; Yoo, Min; Dietrich, Hans H; Holtzman, David M; Zipfel, Gregory Joseph

    2015-02-24

    Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD. PMID:25675483

  13. Influence of Low-Dose Aspirin on Cerebral Amyloid Angiopathy in Mice.

    PubMed

    Hattori, Yorito; Maki, Takakuni; Saito, Satoshi; Yamamoto, Yumi; Nagatsuka, Kazuyuki; Ihara, Masafumi

    2016-04-12

    Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer's dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA. PMID:27079719

  14. Senile plaques and cerebral amyloid angiopathy in an aged California sea lion (Zalophus californianus).

    PubMed

    Takahashi, Erika; Kuribayashi, Hiroyuki; Chambers, James Kenn; Imamura, Emi; Une, Yumi

    2014-09-01

    Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) consisting of β-amyloid (Aβ) are major features in the brain of Alzheimer's disease (AD) patients and elderly humans and animals. In this study, we report the finding of SPs and CAA in an aged sea lion (30 years), which is the first demonstration of AD-related pathological changes in a marine animal. Histologically, SPs were observed at the cerebral cortex, most frequently at the frontal lobe, with two morphologically different types: the small round type and the large granular type. Only the small round SPs were positive for Congo red staining. The SPs were equally immunoreactive to Aβ40 and Aβ42 and were mainly composed of Aβ with an N-terminal pyroglutamate residue at position 3. Amyloid depositions at vessel walls were noted at the meninges and within the parenchyma. Interestingly, double immunofluorescence staining for Aβ40 and Aβ42 showed that the two subtypes were deposited segmentally in different parts of the vessel walls. The lesions observed in the sea lion suggest that Aβ deposition is widely present in various animal species, including marine mammals; however, the peculiar deposits similar to cotton wool plaques and the specific pattern of CAA are characteristic features of this animal. PMID:24779910

  15. Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy-related inflammation.

    PubMed

    Sakai, Kenji; Hayashi, Shintaro; Sanpei, Kazuhiro; Yamada, Masahito; Takahashi, Hitoshi

    2012-10-01

    We report a 75-year-old man with a 3.5-year history of cerebral amyloid angiopathy (CAA)-related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aβ deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aβ-positive blood vessels with double-barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3-ANCA with the pathogenesis of Aβ-associated vasculitis remained unclear, the present case represents a rare example of CAA-related inflammation at the chronic stage. PMID:22188118

  16. Curcumin Reduces Amyloid Fibrillation of Prion Protein and Decreases Reactive Oxidative Stress

    PubMed Central

    Lin, Chi-Fen; Yu, Kun-Hua; Jheng, Cheng-Ping; Chung, Raymond; Lee, Cheng-I

    2013-01-01

    Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer’s disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril formation significantly. Furthermore, we monitored the change in apoptosis and reactive oxygen species (ROS) level upon curcumin treatment in mouse neuroblastoma cells (N2a). Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co-incubation with prion amyloid fibrils. The assays in cell-free mPrP and in N2a cells of this work verified the promising effect of curcumin on the prevention of transmissible neurodegenerative diseases. PMID:25437204

  17. Cerebral ischemia combined with beta-amyloid impairs spatial memory in the eight-arm radial maze task in rats.

    PubMed

    Iwasaki, Katsunori; Egashira, Nobuaki; Hatip-Al-Khatib, Izzettin; Akiyoshi, Yuki; Arai, Takashi; Takagaki, Yuki; Watanabe, Takuya; Mishima, Kenichi; Fujiwara, Michihiro

    2006-06-30

    beta-Amyloid (Abeta), a major component of senile plaques in Alzheimer's disease, has been implicated in neuronal cell death, a characteristic feature of this condition. In our previous experiments using primary cultures of hippocampal neurons, Abeta treatment induced neuronal cell death, displaying morphological characteristics of apoptosis that was significantly enhanced by hypoxia. Based on these results, we developed a simple in vivo rat model of Alzheimer's disease using cerebral ischemia, instead of hypoxia, combined with continuous intracerebroventricular administration of Abeta. The combination of cerebral ischemia and Abeta administration, but not either treatment alone, significantly impaired spatial memory in an eight-arm radial maze. A microdialysis study showed that spontaneous release of acetylcholine (ACh) from the dorsal hippocampus had a tendency to decrease in response to Abeta treatment alone or the combination of ischemia and Abeta. High K(+)-evoked increase in ACh release had a tendency to be inhibited by either ischemia or Abeta treatment alone and was significantly inhibited by the combination of both. Moreover, combination of ischemia and Abeta induced apoptosis of pyramidal neurons in the CA1 region of the hippocampus. Donepezil, a drug currently in clinical use for Alzheimer's disease, improved the impairment of spatial memory induced by cerebral ischemia combined with Abeta. These findings suggest that ischemia is an important factor facilitating the symptoms of Alzheimer's disease, and this model may be useful for developing new drugs for the treatment of Alzheimer's disease. PMID:16729978

  18. Anti-Aβ Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    DiFrancesco, Jacopo C.; Longoni, Martina; Piazza, Fabrizio

    2015-01-01

    Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (Aβ) immunotherapy for Alzheimer’s disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-Aβ autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-Aβ autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID:26441825

  19. Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis

    PubMed Central

    Ielacqua, Giovanna D.; Schlegel, Felix; Füchtemeier, Martina; Xandry, Jael; Rudin, Markus; Klohs, Jan

    2016-01-01

    . We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature. PMID:26834622

  20. New Therapeutic Approaches for Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    Saito, Satoshi; Ihara, Masafumi

    2014-01-01

    Accumulating evidence has shown a strong relationship between Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and cerebrovascular disease. Cognitive impairment in AD patients can result from cortical microinfarcts associated with CAA, as well as the synaptic and neuronal disturbances caused by cerebral accumulations of β-amyloid (Aβ) and tau proteins. The pathophysiology of AD may lead to a toxic chain of events consisting of Aβ overproduction, impaired Aβ clearance, and brain ischemia. Insufficient removal of Aβ leads to development of CAA and plays a crucial role in sporadic AD cases, implicating promotion of Aβ clearance as an important therapeutic strategy. Aβ is mainly eliminated by three mechanisms: (1) enzymatic/glial degradation, (2) transcytotic delivery, and (3) perivascular drainage (3-“d” mechanisms). Enzymatic degradation may be facilitated by activation of Aβ-degrading enzymes such as neprilysin, angiotensin-converting enzyme, and insulin-degrading enzyme. Transcytotic delivery can be promoted by inhibition of the receptor for advanced glycation end products (RAGE), which mediates transcytotic influx of circulating Aβ into brain. Successful use of the RAGE inhibitor TTP488 in Phase II testing has led to a Phase III clinical trial for AD patients. The perivascular drainage system seems to be driven by motive force generated by cerebral arterial pulsations, suggesting that vasoactive drugs can facilitate Aβ clearance. One of the drugs promoting this system is cilostazol, a selective inhibitor of type 3 phosphodiesterase. The clearance of fluorescent soluble Aβ tracers was significantly enhanced in cilostazol-treated CAA model mice. Given that the balance between Aβ synthesis and clearance determines brain Aβ accumulation, and that Aβ is cleared by several pathways stated above, multi-drugs combination therapy could provide a mainstream cure for sporadic AD. PMID:25368578

  1. (68)Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging Aβ Plaques in Cerebral Amyloid Angiopathy.

    PubMed

    Zha, Zhihao; Song, Jin; Choi, Seok Rye; Wu, Zehui; Ploessl, Karl; Smith, Megan; Kung, Hank

    2016-05-18

    Aβ plaques deposited on blood vessels are associated with cerebral amyloid angiopathy (CAA). In an effort to selectively map these Aβ plaques, we are reporting a new series of (68)Ga labeled styrylpyridine derivatives with high molecular weights. In vitro binding to Aβ plaques in post-mortem Alzheimer's disease (AD) brain tissue showed that these (68)Ga labeled bivalent styrylpyridines displayed good affinities and specificity (Ki < 30 nM). In vitro autoradiography using post-mortem AD brain sections showed specific binding of these (68)Ga complexes to Aβ plaques. Biodistribution studies in normal mice showed very low initial brain uptakes (<0.3% dose/g) indicating a low blood-brain barrier (BBB) penetration. The preliminary results suggest that (68)Ga labeled bivalent styrylpyridines may be promising candidates as PET imaging radiotracers for detecting CAA. PMID:27045547

  2. Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

    PubMed Central

    Liao, Fan; Xiao, Qingli; Kraft, Andrew; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David; Lee, Jin-Moo

    2015-01-01

    Background and Purpose Cerebral Amyloid Angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage (ICH) in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and -9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine if spontaneous ICH could be reduced. Methods Tg2576 (n=16) and 5×FAD/ApoE4 knock-in mice (n=16), aged to 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, i.p.) or saline every other day for two months. Brains were extracted and stained with X-34 (to quantify amyloid), Perl’s blue (to quantify hemorrhage), and immunostained to examined Aβ load, gliosis (GFAP, Iba-1), and vascular markers of blood-brain-barrier integrity (ZO-1 and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5×FAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (MMP-9, Nox4, CD45, S-100b, Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in two different mouse models of CAA, supporting the importance of MMP-related and inflammatory pathways in ICH pathogenesis. As an FDA-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related ICH. PMID:25944329

  3. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

    PubMed

    Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D; Shinohara, Motoko; DeTure, Michael; Yamazaki, Yu; Tachibana, Masaya; Atagi, Yuka; Davis, Mary D; Liu, Chia-Chen; Zhao, Na; Painter, Meghan M; Petersen, Ronald C; Fryer, John D; Crook, Julia E; Dickson, Dennis W; Bu, Guojun; Kanekiyo, Takahisa

    2016-08-01

    Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE. PMID:27179972

  4. High levels of circulating beta-amyloid peptide do not cause cerebral beta-amyloidosis in transgenic mice.

    PubMed Central

    Fukuchi, K.; Ho, L.; Younkin, S. G.; Kunkel, D. D.; Ogburn, C. E.; LeBoeuf, R. C.; Furlong, C. E.; Deeb, S. S.; Nochlin, D.; Wegiel, J.; Wisniewski, H. M.; Martin, G. M.

    1996-01-01

    We have established transgenic mice that constitutively overproduce the signal sequence and the 99-amino-acid carboxyl-terminal region of the human beta-amyloid precursor protein. The transgenic mice strongly expressed the transgene in multiple tissues under the control of a cytomegalovirus enhancer/chick beta-actin promoter. There were exceptionally high levels of beta-amyloid peptides in the plasma (approximately 17 times or more compared with the human plasma level). Although some transgenic mice from one founder line developed amyloidosis in the intestine, no neuropathology was found in transgenic mice up to age 29 months. Given the absence of cerebral beta-amyloidosis despite extremely high levels of circulating beta-amyloid peptides in the transgenic mice, the results suggest that local cerebral metabolism of beta-amyloid precursor protein may play a predominant role in cerebral beta-amyloidosis in transgenic mice. Such transgenic mice may be useful for the investigation of the etiology of the disease and for the establishment of therapeutic strategies. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8686746

  5. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    PubMed Central

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. PMID:25355056

  6. Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy.

    PubMed

    Nicolas, Gaël; Wallon, David; Goupil, Claudia; Richard, Anne-Claire; Pottier, Cyril; Dorval, Véronique; Sarov-Rivière, Mariana; Riant, Florence; Hervé, Dominique; Amouyel, Philippe; Guerchet, Maelenn; Ndamba-Bandzouzi, Bebene; Mbelesso, Pascal; Dartigues, Jean-François; Lambert, Jean-Charles; Preux, Pierre-Marie; Frebourg, Thierry; Campion, Dominique; Hannequin, Didier; Tournier-Lasserve, Elisabeth; Hébert, Sébastien S; Rovelet-Lecrux, Anne

    2016-01-01

    Aβ-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Aβ overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3'untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3'UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3'UTR sequence variants as genetic determinants of Aβ-CAA. PMID:25828868

  7. Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach

    PubMed Central

    Reuter, Björn; Venus, Alexander; Grudzenski, Saskia; Heiler, Patrick; Schad, Lothar; Staufenbiel, Matthias; Hennerici, Michael G.; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13), 12 months (n = 7), and 16 months (n = 6), respectively. Controls (n = 16) received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation), compared to 29.3 ± 9.8 in mice with eight months (p = 0.49), 24.9 ± 21.3 with 12 months (p = 0.26), and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27). In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16) compared to controls and also after adjustment for cMB size (p = 0.13). Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed. PMID:26797603

  8. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production.

    PubMed

    Leal, Nuno Santos; Schreiner, Bernadette; Pinho, Catarina Moreira; Filadi, Riccardo; Wiehager, Birgitta; Karlström, Helena; Pizzo, Paola; Ankarcrona, Maria

    2016-09-01

    Mitochondria are physically and biochemically in contact with other organelles including the endoplasmic reticulum (ER). Such contacts are formed between mitochondria-associated ER membranes (MAM), specialized subregions of ER, and the outer mitochondrial membrane (OMM). We have previously shown increased expression of MAM-associated proteins and enhanced ER to mitochondria Ca(2+) transfer from ER to mitochondria in Alzheimer's disease (AD) and amyloid β-peptide (Aβ)-related neuronal models. Here, we report that siRNA knockdown of mitofusin-2 (Mfn2), a protein that is involved in the tethering of ER and mitochondria, leads to increased contact between the two organelles. Cells depleted in Mfn2 showed increased Ca(2+) transfer from ER to mitchondria and longer stretches of ER forming contacts with OMM. Interestingly, increased contact resulted in decreased concentrations of intra- and extracellular Aβ40 and Aβ42 . Analysis of γ-secretase protein expression, maturation and activity revealed that the low Aβ concentrations were a result of impaired γ-secretase complex function. Amyloid-β precursor protein (APP), β-site APP-cleaving enzyme 1 and neprilysin expression as well as neprilysin activity were not affected by Mfn2 siRNA treatment. In summary, our data shows that modulation of ER-mitochondria contact affects γ-secretase activity and Aβ generation. Increased ER-mitochondria contact results in lower γ-secretase activity suggesting a new mechanism by which Aβ generation can be controlled. PMID:27203684

  9. Amyloid-β peptide on sialyl-Lewis(X)-selectin-mediated membrane tether mechanics at the cerebral endothelial cell surface.

    PubMed

    Askarova, Sholpan; Sun, Zhe; Sun, Grace Y; Meininger, Gerald A; Lee, James C-M

    2013-01-01

    Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewis(x) (sLe(x)) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLe(x) and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for Aβ to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, Aβ lowered the overall force of membrane tether formation (Fmtf ), and produced a bimodal population of Fmtf , suggesting subcellular mechanical alterations in membrane tethering. The lower Fmtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both Aβ and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower Fmtf . In addition, these cerebral endothelial alterations induced by Aβ were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for Aβ to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB. PMID:23593361

  10. Amyloid-β Peptide on Sialyl-LewisX-Selectin-Mediated Membrane Tether Mechanics at the Cerebral Endothelial Cell Surface

    PubMed Central

    Askarova, Sholpan; Sun, Zhe; Sun, Grace Y.; Meininger, Gerald A.; Lee, James C-M.

    2013-01-01

    Increased deposition of amyloid-β peptide (Aβ) at the cerebral endothelial cell (CEC) surface has been implicated in enhancement of transmigration of monocytes across the brain blood barrier (BBB) in Alzheimer's disease (AD). In this study, quantitative immunofluorescence microscopy (QIM) and atomic force microscopy (AFM) with cantilevers biofunctionalized by sialyl-Lewisx (sLex) were employed to investigate Aβ-altered mechanics of membrane tethers formed by bonding between sLex and p-selectin at the CEC surface, the initial mechanical step governing the transmigration of monocytes. QIM results indicated the ability for Aβ to increase p-selectin expression at the cell surface and promote actin polymerization in both bEND3 cells (immortalized mouse CECs) and human primary CECs. AFM data also showed the ability for Aβ to increase cell stiffness and adhesion probability in bEND3 cells. On the contrary, Aβ lowered the overall force of membrane tether formation (Fmtf), and produced a bimodal population of Fmtf, suggesting subcellular mechanical alterations in membrane tethering. The lower Fmtf population was similar to the results obtained from cells treated with an F-actin-disrupting drug, latrunculin A. Indeed, AFM results also showed that both Aβ and latrunculin A decreased membrane stiffness, suggesting a lower membrane-cytoskeleton adhesion, a factor resulting in lower Fmtf. In addition, these cerebral endothelial alterations induced by Aβ were abrogated by lovastatin, consistent with its anti-inflammatory effects. In sum, these results demonstrated the ability for Aβ to enhance p-selectin expression at the CEC surface and induce cytoskeleton reorganization, which in turn, resulted in changes in membrane-cytoskeleton adhesion and membrane tethering, mechanical factors important in transmigration of monocytes through the BBB. PMID:23593361

  11. Imaging Findings of Cerebral Amyloid Angiopathy, Aβ-Related Angiitis (ABRA), and Cerebral Amyloid Angiopathy-Related Inflammation: A Single-Institution 25-Year Experience.

    PubMed

    Salvarani, Carlo; Morris, Jonathan M; Giannini, Caterina; Brown, Robert D; Christianson, Teresa; Hunder, Gene G

    2016-05-01

    Vascular inflammation is present in a subset of patients with cerebral amyloid angiopathy (CAA) and has a major influence in determining the disease manifestations. Radiological characterization of this subset is particularly important to achieve early recognition and treatment. We conducted this study to investigate the role of imaging in differentiating CAA with and without inflammation. We reviewed neuroimaging findings for 54 patients seen at Mayo Clinic over 25 years with pathological evidence of CAA and with available neuroimaging at the time of diagnosis. Clinical data were also recorded. Patients were grouped into CAA alone (no vascular inflammation), Aβ-related angiitis or ABRA (angiodestructive inflammation), and CAA-related inflammation or CAA-RI (perivascular inflammation). Imaging findings at presentation were compared among patient subgroups. Radiological features supporting a diagnosis of ABRA or CAA-RI were identified. Radiologic findings at diagnosis were available in 27 patients with CAA without inflammation, 22 with ABRA, and 5 with CAA-RI. On MRI, leptomeningeal disease alone or with infiltrative white matter was significantly more frequent at presentation in patients with ABRA or CAA-RI compared with those with CAA (29.6% vs. 3.7%, P = 0.02; and 40.7% vs. 3.7%, P = 0.002, respectively), whereas lobar hemorrhage was more frequent in patients with CAA (62.3% vs. 7.4%, P = 0.0001). Overall, leptomeningeal involvement at presentation was present in 70.4% of patients with ABRA or CAA-RI and in only 7.4% of patients with CAA (P = 0.0001). The sensitivity and specificity of leptomeningeal enhancement to identify patients with ABRA or CAA-RI were 70.4% and 92.6%, respectively, whereas the positive likelihood ratio (LR) was 9.5. The sensitivity and specificity of intracerebral hemorrhage to identify patients with CAA were 62.9% and 92.6%, respectively, whereas the positive LR was 8.5. Microbleeds were found in 70.4% of patients with

  12. Mapping the landscape of cerebral amyloid angiopathy research: an informetric analysis perspective.

    PubMed

    Charidimou, Andreas; Fox, Zoe; Werring, David J; Song, Min

    2016-03-01

    To quantitatively analyse the research output and major trends in the field of cerebral amyloid angiopathy (CAA) over six decades, from 1954 to 2014, using advanced informetrics methods, we systematically identified CAA-related articles from PubMed, collected metadata and performed productivity analysis, copublication analysis, and network and content analysis over defined time periods. Linear regression was used to investigate these relationships. Changes in CAA research themes (2000-2014) were defined using a topic modelling technique. A total of 2340 CAA papers were published between 1954 and 2014. The mean number (3.03; 95% CI 2.62 to 3.45; p<0.0001) and mean rate (0.13%; 95% CI 0.11% to 0.15%; p<0.0001) of CAA publications increased yearly. Analysis of copublication networks over 5-year periods from 1990 to 2014, revealed a great increase in the total number of connected investigators publishing on CAA (coefficient 16.74; 95% CI 14 to 19.49; p<0.0001) as well as the interactions between them (coefficient 73.53; 95% CI 52.03 to 89.03; p<0.0001). Further analysis of the network characteristics showed that in the past 15 years, copublication networks became not only larger, but also more connected and coherent. Content analysis identified 16 major CAA research themes and their differential evolution in the past 15 years, with the following main trends: (A) limited focus on vascular cognitive impairment; (B) a shift in emphasis towards neuroimaging, cerebral microbleeds and diagnostic aspects and away from pathological aspects; and (3) a reduced emphasis on basic biology apart from an increased focus on mouse models and perivascular drainage. Our study reveals the rapidly developing nature of the CAA research landscape, providing a novel quantitative and objective basis for identifying unmet needs and new directions. Our findings support the idea of a collaborative culture in the field, encouraging international research initiatives. PMID:26071214

  13. Cerebral amyloid angiopathy causing large contralateral hemorrhage during surgery for lobar hemorrhage: a case report.

    PubMed

    Arishima, Hidetaka; Neishi, Hiroyuki; Kodera, Toshiaki; Kitai, Ryuhei; Kikuta, Ken-ichiro

    2015-03-01

    We report a rare case of cerebral amyloid angiopathy (CAA) causing large contralateral hemorrhage during surgery for lobar hemorrhage. A 62-year-old woman presented with lobar hemorrhage in the left frontal and parietal lobes recurring over the previous 1 month. Because we could not detect the origin of the lobar hemorrhage, we performed a biopsy around the lobar hemorrhage site with the removal of a hematoma. During the surgery, we identified acute brain swelling without bleeding from the operative field. Intraoperative computed tomography demonstrated new large lobar hemorrhage of the right parietal lobe, which we could promptly remove. Specimens around hematomas on both sides were pathologically diagnosed as CAA on immunohistochemical examination. After the surgery, she suffered from lobar hemorrhage three times in the space of only 3 months. To the best of our knowledge, there has been no reported case of CAA causing intracranial hemorrhage of another lesion during surgery. Neurosurgeons should know a possibility of intraoperative hemorrhage in surgeries for lobar hemorrhage caused by CAA. PMID:25601180

  14. Cerebral amyloid angiopathy-related atraumatic convexal subarachnoid hemorrhage: an ARIA before the tsunami

    PubMed Central

    Martínez-Lizana, Eva; Carmona-Iragui, María; Alcolea, Daniel; Gómez-Choco, Manuel; Vilaplana, Eduard; Sánchez-Saudinós, María B; Clarimón, Jordi; Hernández-Guillamon, Mar; Munuera, Josep; Gelpi, Ellen; Gómez-Anson, Beatriz; de Juan-Delago, Manel; Delgado-Mederos, Raquel; Montaner, Joan; Ois, Angel; Amaro, Sergi; Blesa, Rafael; Martí-Fàbregas, Joan; Lleó, Alberto; Fortea, Juan

    2015-01-01

    Atraumatic convexal subarachnoid hemorrhage (cSAH) in elderly patients is a rare entity that has been associated with cerebral amyloid angiopathy (CAA) and intracerebral hematomas (ICH). To characterize this entity and to study these associations, 22 patients over 60 with cSAH were included in a multicenter ambispective cohort study. Clinical data, magnetic resonance imaging (MRI) studies, APOE genotyping, and cerebrospinal fluid (CSF) biomarkers were evaluated. Results were compared with data from healthy controls (HC), non-cSAH CAA patients (CAAo), and Alzheimer disease patients. Convexal subarachnoid hemorrhage presented with transient sensory or motor symptoms. At follow-up (median 30.7 months), 5 patients had died, 6 survivors showed functional disability (modified Rankins Scale (mRS)>2), and 12 cognitive impairment. Four patients had prior ICH and six had an ICH during follow-up. CSF-Aß40 and Aß42 levels were lower in cSAH and CAAo compared with HC. Convexal subarachnoid hemorrhage presented an APOE-ɛ2 overrepresentation and CAAo had an APOE-ɛ4 overrepresentation. On MRI, all patients fulfilled CAA-modified Boston criteria and 9 showed cortical ischemia in the surrounding cortex or the vicinity of superficial siderosis. The neuropathologic study, available in one patient, showed severe CAA and advanced Alzheimer-type pathology. Convexal subarachnoid hemorrhage in the elderly is associated with cognitive impairment and lobar ICH occurrence. Our findings support the existence of an underlying CAA pathology. PMID:25735919

  15. Cerebral Amyloid Angiopathy: An Important Differential Diagnosis of Stroke in the Elderly

    PubMed Central

    AZMIN, Shahrul; OSMAN, Syazarina Sharis; MUKARI, Shahizon; SAHATHEVAN, Ramesh

    2015-01-01

    Cerebral amyloid angiopathy (CAA) accounts for approximately 10–20% of spontaneous intracerebral haemorrhage (ICH). This figure is thought to be higher in the elderly population. With the increasing life expectancy of our population, we anticipate that the prevalence of CAA- related ICH will increase in tandem. Although CAA-related ICH and hypertension-related ICH are distinct entities based on histopathology and imaging, the clinical presentation of the two conditions is similar. The use of brain computed tomography (CT) scans remain the ICH imaging modality of choice in Malaysia due to its availability, cost, and sensitivity in detecting acute bleeds. On the other hand, the use of brain magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) sequencing enables the clinician to determine the presence of chronic blood products in the brain, especially clinically silent microbleeds associated with CAA. However, the use of brain MRI scans in our country is limited and leads to a blurring of lines when differentiating between hypertension-related ICH and CAA-related ICH. How this misrepresentation affects the management of these conditions is unclear. In this study, we present two cases of ICH to illustrate this point and to serve as a springboard to question current practice and promote discussion. PMID:25892953

  16. Cerebral Palsy Symptoms in Children Decreased Following Massage Therapy

    ERIC Educational Resources Information Center

    Hernandez-Reif, Maria; Field, Tiffany; Largie, Shay; Diego, Miguel; Manigat, Natasha; Seoanes, Jacqueline; Bornstein, Joan

    2005-01-01

    Twenty young children (mean age = 32 months) with cerebral palsy (CP) recruited from early intervention programs received 30 minutes of massage or reading twice weekly for 12 weeks. The children receiving massage therapy showed fewer physical symptoms including reduced spasticity, less rigid muscle tone overall and in the arms, and improved fine…

  17. Unusual cerebral vascular prion protein amyloid distribution in scrapie-infected transgenic mice expressing anchorless prion protein

    PubMed Central

    2013-01-01

    Background In some prion diseases, misfolded aggregated protease-resistant prion protein (PrPres) is found in brain as amyloid, which can cause cerebral amyloid angiopathy. Small diffusible precursors of PrPres amyloid might flow with brain interstitial fluid (ISF), possibly accounting for the perivascular and intravascular distribution of PrPres amyloid. We previously reported that PrPres amyloid in scrapie-infected transgenic mice appeared to delay clearance of microinjected brain ISF tracer molecules. Results Here we studied distribution of PrPres amyloid on capillaries, arteries and veins to test whether vascular specificity of PrPres corresponded to distribution of ISF tracer molecules. To distinguish PrPres-positive arteries from veins and capillaries, scrapie-infected mouse brains were studied by immunodetection of alpha smooth muscle actin. ISF was studied using fluorescein-labeled ovalbumin microinjected into brain as a tracer. In infected preclinical or clinical mice, PrPres was found mostly on capillaries (73-78%). Lower levels were found on arteries (11-14%) and veins (11-13%). Compared to PrPres, ISF tracer was found at higher levels on capillaries (96-97%), and the remaining tracer was found at a skewed ratio of 4 to 1 on arteries and veins respectively. Conclusions PrPres association with blood vessels suggested that ISF flow might transport diffusible PrPres precursor molecules to perivascular sites. However, the different vascular specificity of PrPres and ISF tracer indicated that ISF flow did not alone control PrPres dissemination. Possibly blood vessel basement membrane (BM) components, such as glucosaminoglycans, might concentrate small PrPres aggregates and serve as scaffolds for PrP conversion on multiple vessel types. PMID:24252347

  18. Multidentate 18F-polypegylated styrylpyridines as imaging agents for Aβ plaques in cerebral amyloid angiopathy (CAA)

    PubMed Central

    Zha, Zhihao; Choi, Seok Rye; Ploessl, Karl; Lieberman, Brian P.; Qu, Wenchao; Hefti, Franz; Mintun, Mark; Skovronsky, Daniel; Kung, Hank F.

    2011-01-01

    Beta-amyloid plaques (Aβ plaques) in the brain are associated with cerebral amyloid angiopathy (CAA). Imaging agents that could target the Aβ plaques in the living human brain would be potentially valuable as biomarkers in patients with CAA. A new series of 18F styrylpyridine derivatives with high molecular weights for selectively targeting Aβ plaques in the blood vessels of the brain, but excluded from the brain parenchyma is reported. The styrylpyridine derivatives, 8a–c, display high binding affinities and specificity to Aβ plaques (Ki = 2.87 nM, 3.24 and 7.71 nM, respectively). In vitro autoradiography of [18F]8a shows labeling of β-amyloid plaques associated with blood vessel walls in human brain sections of subjects with CAA, and also in the tissue of AD brain sections. The results suggest that [18F]8a may be a useful PET imaging agent for selectively detecting Aβ plaques associated with cerebral vessels in the living human brain. PMID:22011144

  19. MMP-2/MMP-9 plasma level and brain expression in cerebral amyloid angiopathy-associated hemorrhagic stroke.

    PubMed

    Hernandez-Guillamon, Mar; Martinez-Saez, Elena; Delgado, Pilar; Domingues-Montanari, Sophie; Boada, Cristina; Penalba, Anna; Boada, Mercè; Pagola, Jorge; Maisterra, Olga; Rodriguez-Luna, David; Molina, Carlos A; Rovira, Alex; Alvarez-Sabin, José; Ortega-Aznar, Arantxa; Montaner, Joan

    2012-03-01

    Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in β-amyloid (Aβ)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aβ-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding. PMID:21707819

  20. Distribution of precursor amyloid-. beta. -protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques

    SciTech Connect

    Lewis, D.A.; Higgins, G.A.; Young, W.G.; Goldgaber, D.; Gajdusek, D.C.; Wilson, M.C.; Morrison, J.H.

    1988-03-01

    Neurofibrillary tangles (NFT) and neuritic plaques (NP), two neuropathological markers of Alzheimer disease, may both contain peptide fragments derived from the human amyloid ..beta.. protein. However, the nature of the relationship between NFT and NP and the source of the amyloid ..beta.. proteins found in each have remained unclear. The authors used in situ hybridization techniques to map the anatomical distribution of precursor amyloid-..beta..-protein mRNA in the neocortex of brains from three subjects with no known neurologic disease and from five patients with Alzheimer disease. In brains from control subjects, positively hybridizing neurons were present in cortical regions and layers that contain a high density of neuropathological markers in Alzheimer disease, as well as in those loci that contain NP but few NFT. Quantitative analyses of in situ hybridization patterns within layers III and V of the superior frontal cortex revealed that the presence of high numbers of NFT in Alzheimer-diseased brains was associated with a decrease in the number of positively hybridizing neurons compared to controls and Alzheimer-diseased brains with few NFT. These findings suggest that the expression of precursor amyloid-..beta..-protein mRNA may be a necessary but is clearly not a sufficient prerequisite for NFT formation. In addition, these results may indicate that the amyloid ..beta.. protein, present in NP in a given region or layer of cortex, is not derived from the resident neuronal cell bodies that express the mRNA for the precursor protein.

  1. Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

    PubMed Central

    Zussy, Charleine; Brureau, Anthony; Delair, Brice; Marchal, Stephane; Keller, Emeline; Ixart, Guy; Naert, Gaelle; Meunier, Johann; Chevallier, Nathalie; Maurice, Tangui; Givalois, Laurent

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25–35 (Aβ25-35) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ25-35 peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ25-35 decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ25-35, the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ25-35 injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD. PMID:21703413

  2. Role of hypotension in decreasing cerebral blood flow in porcine endotoxemia

    SciTech Connect

    Miller, C.F.; Breslow, M.J.; Shapiro, R.M.; Traystman, R.J. )

    1987-10-01

    The role of reduced arterial blood pressure (MAP) in decreasing cerebral blood flow (CBF) during endotoxemia was studied in pentobarbital-anesthetized pigs. Microspheres were used to measure regional CBF changes during MAP manipulations in animals with and without endotoxin. Endotoxin decreased MAP to 50 mmHg and decreased blood flow to the cortex and cerebellum without affecting cerebral cortical oxygen consumption (CMRo{sub 2}). Elevating MAP from 50 to 70 mmHg during endotoxemia with norepinephrine did not change cortical blood flow or CMRo{sub 2} but increased cerebellar blood flow. Brain stem blood flow was not affected by endotoxin or norepinephrine. When MAP was decreased to 50 mmHg by hemorrhage without endotoxin, no change in blood flow to cortex, cerebellum, or brain stem was observed from base-line levels. These results suggest that decreased MAP below a lower limit for cerebral autoregulation does not account for the decreased CBF observed after endotoxin.

  3. Oxidative damage of 14-3-3 zeta and gamma isoforms in Alzheimer's disease and cerebral amyloid angiopathy.

    PubMed

    Santpere, G; Puig, B; Ferrer, I

    2007-06-01

    Previous studies have shown oxidative damage resulting from amyloid Abeta exposure to cultured cells and in murine models. A target of oxidation is 14-3-3 which comprises a group of proteins involved in kinase activation and chaperone activity. The present study shows glycoxidative damage, as revealed with mono and bi-dimensional gel electrophoresis and Western blotting, followed by in-gel digestion and mass spectrometry, in the frontal cortex in Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), a neurodegenerative disease with deposition of Abeta in cerebral blood vessels and in diffuse plaques unaccompanied by intraneuronal hyper-phosphorylated tau deposition. malondialdehyde-lysine (MDA-Lys)-, but not 4-hydroxy-2-nonenal (HNE)-immunoreactive adducts, and N-carboxyethyl-lysine (CEL), but not N-carboxymethyl-lysine (CML)-products, were present in 14-3-3 involving zeta and gamma isoforms in both AD and CAA. These findings demonstrate that 14-3-3 glyco- and lipoxidation occurs in AD and CAA, probably as a direct consequence of Abeta deposition. PMID:17445990

  4. Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation.

    PubMed

    Fine, Jared M; Renner, Daniel B; Forsberg, Anna C; Cameron, Rachel A; Galick, Benjamin T; Le, Clint; Conway, Patrick M; Stroebel, Benjamin M; Frey, William H; Hanson, Leah R

    2015-01-01

    In addition to the hallmark accumulation of amyloid and hyper-phosphorylation of tau, brain changes in Alzheimer's disease are multifactorial including inflammation, oxidative stress, and metal dysregulation. Metal chelators have been explored as a less well known approach to treatment. One chelator currently being developed is deferoxamine (DFO), administered via the intranasal (IN) route. In the current study, APP/PS1 amyloid mice were treated with a chronic, low dose of IN DFO, subjected to a rigorous battery of behavior tests, and the mechanism of action was examined. Mice were treated 3x/week with 0.24 C IN DFO for 18 weeks from 36 to 54 weeks of age, 4 weeks of behavior tests were performed that included both working and reference memory, anxiolytic and motor behaviors, and finally brain tissues were analyzed for amyloid, protein oxidation, and other proteins affected by DFO. We found that IN DFO treatment significantly decreased loss of both reference and working memory in the Morris and radial arm water mazes (p < 0.05), and also decreased soluble Aβ40 and Aβ42 in cortex and hippocampus (p < 0.05). Further, IN DFO decreased activity of GSK3β, and led to decreases in oxidative stress (p < 0.05). These data demonstrate that low doses of IN DFO can modify several targets along the multiple pathways implicated in the neuropathology of Alzheimer's, making it an attractive candidate for the treatment of this heterogeneous disease. PMID:25445365

  5. Development of Cerebral Microbleeds in the APP23-Transgenic Mouse Model of Cerebral Amyloid Angiopathy—A 9.4 Tesla MRI Study

    PubMed Central

    Reuter, Björn; Venus, Alexander; Heiler, Patrick; Schad, Lothar; Ebert, Anne; Hennerici, Michael G.; Grudzenski, Saskia; Fatar, Marc

    2016-01-01

    Background: Cerebral amyloid angiopathy (CAA) is characterized by extracellular deposition of amyloid β (Aβ) around cerebral arteries and capillaries and leads to an increased risk for vascular dementia, spontaneous lobar hemorrhage, convexal subarachnoid hemorrhage, and transient focal neurological episodes, which might be an indicator of imminent spontaneous intracerebral hemorrhage. In CAA cerebral microbleeds (cMBs) with a cortical/juxtacortical distribution are frequently observed in standard magnetic resonance imaging (MRI). In vivo MRI of transgenic mouse models of CAA may serve as a useful tool to investigate translational aspects of the disease. Materials and Methods: APP23-transgenic mice demonstrate cerebrovascular Aβ deposition with subsequent neuropathological changes characteristic for CAA. We performed a 9.4 Tesla high field MRI study using T2, T2* and time of flight-magnetic resonance angiograpy (TOF-MRA) sequences in APP23-transgenic mice and wildtype (wt) littermates at the age of 8, 12, 16, 20 and 24 months, respectively. Numbers, size, and location of cMBs are reported. Results: T2* imaging demonstrated cMBs (diameter 50–300 μm) located in the neocortex and, to a lesser degree, in the thalamus. cMBs were detected at the earliest at 16 months of age. Numbers increased exponentially with age, with 2.5 ± 2 (median ± interquartilrange) at 16 months, 15 ± 6 at 20 months, and 31.5 ± 17 at 24 months of age, respectively. Conclusion: We report the temporal and spatial development of cMBs in the aging APP23-transgenic mouse model which develops characteristic pathological patterns known from human CAA. We expect this mouse model to serve as a useful tool to non-invasively monitor mid- and longterm translational aspects of CAA and to investigate experimental therapeutic strategies in longitudinal studies. PMID:27458375

  6. Hereditary cystatin C (gamma-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage.

    PubMed

    Jensson, O; Gudmundsson, G; Arnason, A; Blöndal, H; Petursdottir, I; Thorsteinsson, L; Grubb, A; Löfberg, H; Cohen, D; Frangione, B

    1987-08-01

    Hereditary CNS amyloid angiopathy occurring in Icelanders is the first human disorder known to be caused by deposition of cystatin C amyloid fibrils in the walls of the brain arteries leading to single or or multiple strokes with fatal outcome. One or more affected members have been verified by histological examination in 8 families containing 127 affected. These originated from the same geographic area. Abnormally low value of cystatin C found in the cerebrospinal fluid of those affected can be used to support or make diagnosis of this disease, also in asymptomatic relatives. By amino acid sequence analysis the amyloid fibrils in the patients are found to be a variant of cystatin C (gamma-trace), a major cysteine proteinase inhibitor. The variant protein has an amino acid substitution (glutamine for leucine) at position 58 in the amyloid molecule. It is postulated that a point mutation has occurred leading to production of amyloidogenic protein causing the disorder. PMID:3673496

  7. beta-amyloid protein of Alzheimer's disease is found in cerebral and spinal cord vascular malformations.

    PubMed Central

    Hart, M. N.; Merz, P.; Bennett-Gray, J.; Menezes, A. H.; Goeken, J. A.; Schelper, R. L.; Wisniewski, H. M.

    1988-01-01

    Congo/Red deposition with birefringence to polarized light was demonstrated focally in cerebrovascular malformations removed surgically from 4 older patients (ages 85, 74, 74, and 63), and in a spinal cord vascular malformation in a 76-year-old patient. Lesser degrees of Congophilic change were observed in cerebrovascular malformations screened from 4 of 10 patients between the ages of 30 and 59. No Congophilic change was seen in 10 cerebrovascular malformations removed from patients under 30 years of age. Congophilic areas in all cases decorated with W-2 and 85/45 polyclonal antibodies raised to peptide sequences of cerebrovascular beta-amyloid and beta-amyloid of senile plaques from patients with Alzheimer's disease. Thus, the amyloid in these vascular malformations is immunologically related to beta-amyloid protein. This finding provides another indication that vascular beta-amyloid deposition is not specific for Alzheimer's disease and suggests that an existing abnormality of vessels may be a predisposing factor. Images Figure 1 Figure 2A Figure 2B Figure 3 Figure 4 PMID:3293463

  8. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer's models.

    PubMed

    Busche, Marc Aurel; Grienberger, Christine; Keskin, Aylin D; Song, Beomjong; Neumann, Ulf; Staufenbiel, Matthias; Förstl, Hans; Konnerth, Arthur

    2015-12-01

    Among the most promising approaches for treating Alzheimer's disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies. PMID:26551546

  9. Memantine treatment decreases levels of secreted Alzheimer's amyloid precursor protein (APP) and amyloid beta (A beta) peptide in the human neuroblastoma cells.

    PubMed

    Ray, Balmiki; Banerjee, Pradeep K; Greig, Nigel H; Lahiri, Debomoy K

    2010-02-01

    Memantine, an uncompetitive NMDA receptor antagonist, is a FDA-approved drug used for the treatment of moderate-to-severe Alzheimer's disease (AD). Several studies have documented protective roles of memantine against amyloid beta (A beta) peptide-mediated damage to neurons in both in vitro and in vivo models. Memantine is also effective in reducing amyloid burden in the brain of APP transgenic mice. However, the exact mechanism by which memantine provides protection against A beta-mediated neurodegenerative cascade, including APP metabolism, remains to be elucidated. Herein, we investigated the effect of memantine on levels of the secreted form of A beta precursor protein (APP), secreted A beta and cell viability markers under short/acute conditions. We treated neuronal SK-N-SH cells with 10 microM memantine and measured levels of secreted total APP (sAPP), APP alpha isoform and A beta((1-40)) in a time dependent manner for up to 24h. Memantine significantly decreased the levels of the secreted form of sAPP, sAPP alpha and A beta((1-40)) compared to vehicle treated cells. This change started as early as 8h and continued for up to 24h of drug treatment. Unlike sAPP, a slight non-significant increase in total intracellular APP level was observed in 24-h treated memantine cells. Taken together, these results suggest a role for memantine in the transport or trafficking of APP molecules away from the site of their proteolytic cleavage by the secretase enzymes. Such a novel property of memantine warrants further study to define its therapeutic utility. PMID:19948208

  10. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    PubMed

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD. PMID:26324099

  11. Icariin Decreases the Expression of APP and BACE-1 and Reduces the β-amyloid Burden in an APP Transgenic Mouse Model of Alzheimer's Disease

    PubMed Central

    Zhang, Lan; Shen, Cong; Chu, Jin; Zhang, Ruyi; Li, Yali; Li, Lin

    2014-01-01

    Objective: The purpose of this study was to investigate the effects and pharmacological mechanisms of icariin, which is the main component in the traditional Chinese herb Epimedium, on β-amyloid (Aβ) production in an amyloid precursor protein (APP) transgenic (Tg) mouse model of Alzheimer's disease (AD). Methods: APPV717I Tg mice were randomly divided into a model group and icariin-treated (30 and 100 μmol/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition tests. Aβ contents were measured by enzyme-linked immunosorbent assays and immunohistochemistry. Amyloid plaques were detected by Congo red staining and Bielschowsky silver staining. The levels of expression of APP and β-site APP-cleaving enzyme 1 (BACE-1) were measured by western blotting and immunohistochemistry. Results: Ten-month-old Tg mice showed obvious learning-memory impairments, and significant increases in Aβ contents, amyloid plaques, and APP and BACE-1 levels in the hippocampus. The intragastric administration of icariin to Tg mice for 6 months (from 4 to 10 months of age) improved the learning-memory abilities and significantly decreased the Aβ contents, amyloid plaques, and APP and BACE-1 levels in the hippocampus. Conclusion: Icariin reduced the Aβ burden and amyloid plaque deposition in the hippocampus of APP transgenic mice by decreasing the APP and BACE-1 levels. These novel findings suggest that icariin may be a promising treatment in patients with AD. PMID:24550686

  12. Osthole decreases beta amyloid levels through up-regulation of miR-107 in Alzheimer's disease.

    PubMed

    Jiao, Yanan; Kong, Liang; Yao, Yingjia; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui; Yang, Jingxian

    2016-09-01

    Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). Although osthole has been shown to neuroprotective activity in AD, the exact molecular mechanism of its neuroprotective effects has not yet been fully elucidated. Recently, microRNAs (miRNAs) have been reported to regulate multiple aspects of AD development and progression, indicating that targeting miRNAs could be a novel strategy to treat AD. In the current study, we investigated whether a natural coumarin derivative osthole could up-regulate miR-107, resulting in facilitating the cells survival, reducing LDH leakage, inhibiting apoptosis and reducing beta amyloid (Aβ) production in AD. We found that osthole treatment significantly up-regulate miR-107 expression and inhibited BACE1, one of the targets of miR-107. Administration of osthole to APP/PS1 transgenic mice resulted in a significant improvement in learning and memory function, which was associated with a significant a decrease in Aβ in the hippocampal and cortex region of the brain. Our findings demonstrated that osthole plays a neuroprotective activity role in part through up-regulate miR-107 in AD. PMID:27143098

  13. Sleep apnea termination decreases cerebral blood volume: a near-infrared spectroscopy case study

    NASA Astrophysics Data System (ADS)

    Virtanen, Jaakko; Noponen, Tommi; Salmi, Tapani; Toppila, Jussi; Meriläinen, Pekka

    2009-07-01

    Medical near-infrared spectroscopy (NIRS) can be used to estimate cerebral haemodynamic changes non-invasively. Sleep apnea is a common sleep disorder where repetitive pauses in breathing decrease the quality of sleep and exposes the individual to various health problems. We have measured oxygenated and deoxygenated haemoglobin concentration changes during apneic events in sleep from the forehead of one subject using NIRS and used principal component analysis to extract extracerebral and cortical haemodynamic changes from NIRS signals. Comparison of NIRS signals with EEG, bioimpedance, and pulse oximetry data suggests that termination of apnea leads to decreases in cerebral blood volume and flow that may be related to neurological arousal via neurovascular coupling.

  14. Decreased IDE and IGF2 expression but increased Aβ40 in the cerebral cortex of mouse pups by early life lead exposure.

    PubMed

    Li, Ning; Yang, Guojun; Wang, Yueying; Qiao, Mingwu; Zhang, Pingan; Shao, Jianfeng; Yang, Guoyu

    2016-03-01

    As the abbreviation of plumbum and a chemical symbol for lead, Pb produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. However, the mechanism of neurotoxicity of Pb exposure is unclear. The present study was undertaken to investigate the effects of maternal lead exposure on expression of insulin-degrading enzyme (IDE),insulin-like growth factor 2 (IGF2) and beta amyloid protein 40 (Aβ40) in the cerebral cortex of mice offspring. Lead exposure initiated from beginning of gestation to weaning. Lead acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.2% and 0.5% groups respectively. On the 21st postnatal day, On the PND21, the learning and memory ability were tested by water maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IDE, IGF2 and Aβ40 in cerebral cortex was examined by immunohistochemistry, immunofluorescence and western blotting. The lead levels in blood and cerebral cortex of all lead exposure groups were significantly higher than that of the control group (P<0.05). In water maze test, the performances of 0.5% and 1% lead exposure groups were worse than that of the control group (P<0.05).The expression of IDE and IGF2 was decreased, but Aβ40 was increased in lead exposed groups than that of the control group (P<0.05). The decreased expression of IDE and IGF2 and increased expression of Aβ40 in the cerebral cortex of pups may contribute to the neurotoxicity associated with maternal Pb exposure. PMID:26791739

  15. Cerebral white matter lesions – associations with Aβ isoforms and amyloid PET

    PubMed Central

    van Westen, Danielle; Lindqvist, Daniel; Blennow, Kaj; Minthon, Lennart; Nägga, Katarina; Stomrud, Erik; Zetterberg, Henrik; Hansson, Oskar

    2016-01-01

    Small vessel disease (SVD) and amyloid deposition may promote each other, with a potential association between SVD and altered production or clearance of β-amyloid (Aβ) affecting its cleavage products. We investigated the relationship between SVD, multiple isoforms of Aβ in cerebrospinal fluid (CSF) and cortical Aβ in 831 subjects with cognitive performance ranging from normal to Alzheimer’s disease (AD) (the Swedish BioFINDER study). SVD was estimated as white matter lesions (WML) and lacunes. 18F-flutemetamol PET was performed in 321 subjects. Lower CSF levels of Aβ38 and Aβ40 were consistently associated with increased WML in all subgroups, while lower levels of CSF Aβ42 were associated with WML mainly in AD. CSF Aβ38 and Aβ40 were associated with regional WML in all regions, while CSF Aβ42 was associated with temporal WML only. A composite measure of 18F-flutemetamol uptake was not associated with WML, and regional 18F-flutemetamol uptake only with temporal WML. Lacunes were not associated with Aβ isoforms nor 18F-flutemetamol uptake. Our results suggest that WML may be associated with alterations in the production or clearance of Aβ species, particularly of Aβ38 and Aβ40. However, in AD cases, Aβ42 pathology might be associated with WML, especially in the temporal lobe. PMID:26856756

  16. An In Vivo Evaluation of Cerebral Cortical Amyloid with [18F]Flutemetamol Using Positron Emission Tomography Compared with Parietal Biopsy Samples in Living Normal Pressure Hydrocephalus Patients

    PubMed Central

    Wong, Dean F.; Moghekar, Abhay R.; Rigamonti, Daniele; Brašić, James R.; Rousset, Olivier; Willis, William; Buckley, Chris; Smith, Adrian; Gok, Beril; Sherwin, Paul; Grachev, Igor D.

    2014-01-01

    Purpose The primary objectives of this study were to assess the safety of [18F]flutemetamol injection and determine the level of association between the quantitative estimates of brain uptake of [18F] flutemetamol and the quantitative immunohistochemical (IHC) estimates of amyloid levels in cerebral cortex biopsies obtained during shunt placement in patients with normal pressure hydrocephalus (NPH). Procedures Parietal lobe biopsies were obtained from 12 subjects (mean (SD), 71 (8.1) years), during shunt placement for NPH. Shunt procedures and biopsies were performed within 8 weeks after the positron emission tomography (PET) imaging, and followed by a computed tomography scan. The quantitative estimates of the brain uptake of [18F]flutemetamol (standard uptake value ratios (SUVRs)) from the biopsy site, contralateral to the biopsy site, and composite were made from the analysis of PET images. The quantitative IHC levels of amyloid load were estimated using a monoclonal antiamyloid β antibody, 4 G8 (in percent area), as the standard of truth (N=8, of which 5 had full histopathology staining). The primary analysis determined the level of association between the SUVR (with cerebellum as the reference region) from the biopsy site, and the level of amyloid was determined from IHC estimates of amyloid in the biopsy sample. Results [18F]Flutemetamol injection was found to be well tolerated. The biopsied area well represented the amyloid deposition throughout the cortex in this small sample. The biopsy site SUVR was significantly correlated with the biopsy specimen amyloid β level (expressed as percent of biopsy specimen area staining with 4 G8). The full model was significant (p=0.0174). In the secondary efficacy analyses, contralateral (to biopsy site) and composite SUVR values correlated significantly with the percent of biopsy specimen staining for amyloid β based on 4 G8. Blinded visual [18F]flutemetamol image interpretations showed a sensitivity of 100 % and a

  17. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease.

    PubMed

    Varvel, Nicholas H; Grathwohl, Stefan A; Degenhardt, Karoline; Resch, Claudia; Bosch, Andrea; Jucker, Mathias; Neher, Jonas J

    2015-10-19

    Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD. PMID:26458770

  18. Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds.

    PubMed

    Joseph-Mathurin, Nelly; Dorieux, Olène; Trouche, Stéphanie G; Boutajangout, Allal; Kraska, Audrey; Fontès, Pascaline; Verdier, Jean-Michel; Sigurdsson, Einar M; Mestre-Francés, Nadine; Dhenain, Marc

    2013-11-01

    Anti-amyloid beta (Aβ) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Aβ1-42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aβ1-42 or Aβ-derivative (K6Aβ1-30). We followed anti-Aβ40 immunoglobulin G and M responses and Aβ levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aβ1-42 immunogen. This treatment induced immune response and increased Aβ levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aβ-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials. PMID:23796662

  19. Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer's Disease

    PubMed Central

    Biron, Kaan E.; Dickstein, Dara L.; Gopaul, Rayshad; Jefferies, Wilfred A.

    2011-01-01

    Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration. PMID:21909359

  20. Absence of PIttsburgh Compound B Detection of CerebralAmyloid Beta in a Patient With Clinical, Cognitive, and Cerebrospinal FluidMarkers of Alzheimer Disease

    PubMed Central

    Cairns, Nigel J.; Ikonomovic, Milos D.; Benzinger, Tammie; Storandt, Martha; Fagan, Anne M; Shah, Arti; Schmidt, Robert E.; Perry, Arie; Reinwald, Lisa Taylor; Carter, Deborah; Felton, Angela; Holtzman, David M.; Mintun, Mark A.; Klunk, William E.; Morris, John C.

    2009-01-01

    Objective To determine the temporal relationships of clinical, cognitive, Pittsburgh Compound-B (PiB) amyloid imaging, and cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD). Design A case report of a longitudinally assessed participant in a memory and aging study who had serial clinical and psychometric assessments over 6 years, in addition to PiB imaging and CSF biomarker assays, prior to coming to autopsy. Setting Alzheimer’s Disease Research Center Findings An 85-year old individual was cognitively normal at his initial and next 3 annual assessments. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB-PET amyloid imaging was negative at age 88.5 years, but at age 89.5 years there was reduced amyloid-beta 42 (Aβ42) and elevated levels of tau in the CSF. At his 6th assessment, when he was 90 years old, he was diagnosed with very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse Aβ plaques, sufficient to fulfill Khachaturian neuropathologic criteria for AD, but neuritic plaques and neurofibrillary tangles were sparse. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB-PET-binding was below the level needed for in vivo detection. Conclusion Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral Aβ with amyloid imaging agents such as PiB, which primarily label fibrillar Aβ plaques. PMID:20008664

  1. Electromagnetic Treatment to Old Alzheimer's Mice Reverses β-Amyloid Deposition, Modifies Cerebral Blood Flow, and Provides Selected Cognitive Benefit

    PubMed Central

    Arendash, Gary W.; Mori, Takashi; Dorsey, Maggie; Gonzalez, Rich; Tajiri, Naoki; Borlongan, Cesar

    2012-01-01

    Few studies have investigated physiologic and cognitive effects of “long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25–1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21–27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF “ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during “ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

  2. APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

    PubMed Central

    Ramanan, Vijay K.; Risacher, Shannon L.; Nho, Kwangsik; Kim, Sungeun; Swaminathan, Shanker; Shen, Li; Foroud, Tatiana M.; Hakonarson, Hakon; Huentelman, Matthew J.; Aisen, Paul S.; Petersen, Ronald C.; Green, Robert C.; Jack, Clifford R.; Koeppe, Robert A.; Jagust, William J.; Weiner, Michael W.; Saykin, Andrew J.

    2013-01-01

    Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum. PMID:23419831

  3. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia.

    PubMed

    Adibhatla, Rao Muralikrishna; Hatcher, James F

    2003-08-01

    Neuroprotection by citicoline (CDP-choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A(2) (PLA(2)) activity in relation to the attenuation of hydroxyl radical (OH.) generation after transient forebrain ischemia of gerbil. PLA(2) activity (requires mM Ca(2+)) increased significantly (P < 0.05) in both membrane (50.2 +/- 2.2 pmol/min/mg protein compared to sham 35.9 +/- 3.2) and mitochondrial fractions (77.0 +/- 1.2 pmol/min/mg protein compared to sham 33.9 +/- 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. +/- 2.2 and mitochondria, 41.9 +/- 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA(2) activity, and thus citicoline as such is not a PLA(2) inhibitor. Ischemia/reperfusion resulted in significant OH. generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3-dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 +/- 0.23; sham, 2.56 +/- 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 +/- 0.35). These results suggest that citicoline affects PLA(2) stimulation and decreases OH. generation after transient cerebral ischemia. PMID:12868064

  4. Cerebral blood flow velocity and cranial fluid volume decrease during +Gz acceleration

    NASA Technical Reports Server (NTRS)

    Kawai, Y.; Puma, S. C.; Hargens, A. R.; Murthy, G.; Warkander, D.; Lundgren, C. E.

    1997-01-01

    Cerebral blood flow (CBF) velocity and cranial fluid volume, which is defined as the total volume of intra- and extracranial fluid, were measured using transcranial Doppler ultrasonography and rheoencephalography, respectively, in humans during graded increase of +Gz acceleration (onset rate: 0.1 G/s) without straining maneuvers. Gz acceleration was terminated when subjects' vision decreased to an angle of less than or equal to 60 degrees, which was defined as the physiological end point. In five subjects, mean CBF velocity decreased 48% from a baseline value of 59.4 +/- 11.2 cm/s to 31.0 +/- 5.6 cm/s (p<0.01) with initial loss of peripheral vision at 5.7 +/- 0.9 Gz. On the other hand, systolic CBF velocity did not change significantly during increasing +Gz acceleration. Cranial impedance, which is proportional to loss of cranial fluid volume, increased by 2.0 +/- 0.8% above the baseline value at the physiological end point (p<0.05). Both the decrease of CBF velocity and the increase of cranial impedance correlated significantly with Gz. These results suggest that +Gz acceleration without straining maneuvers decreases CBF velocity to half normal and probably causes a caudal fluid shift from both intra- and extracranial tissues.

  5. 1α,25-Dihydroxyvitamin D3 reduces cerebral amyloid-β accumulation and improves cognition in mouse models of Alzheimer's disease.

    PubMed

    Durk, Matthew R; Han, Kyung; Chow, Edwin C Y; Ahrens, Rosemary; Henderson, Jeffrey T; Fraser, Paul E; Pang, K Sandy

    2014-05-21

    We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-β (Aβ) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble Aβ levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH)2D3 during the period of plaque formation reduced soluble and insoluble plaque-associated Aβ, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH)2D3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease. PMID:24849345

  6. Decreased and Increased Anisotropy along Major Cerebral White Matter Tracts in Preterm Children and Adolescents

    PubMed Central

    Ben-Shachar, Michal; Feldman, Heidi M.

    2015-01-01

    Premature birth is highly prevalent and associated with neurodevelopmental delays and disorders. Adverse outcomes, particularly in children born before 32 weeks of gestation, have been attributed in large part to white matter injuries, often found in periventricular regions using conventional imaging. To date, tractography studies of white matter pathways in children and adolescents born preterm have evaluated only a limited number of tracts simultaneously. The current study compares diffusion properties along 18 major cerebral white matter pathways in children and adolescents born preterm (n = 27) and full term (n = 19), using diffusion magnetic resonance imaging and tractography. We found that compared to the full term group, the preterm group had significantly decreased FA in segments of the bilateral uncinate fasciculus and anterior segments of the right inferior fronto-occipital fasciculus. Additionally, the preterm group had significantly increased FA in segments of the right and left anterior thalamic radiations, posterior segments of the right inferior fronto-occipital fasciculus, and the right and left inferior longitudinal fasciculus. Increased FA in the preterm group was generally associated with decreased radial diffusivity. These findings indicate that prematurity-related white matter differences in later childhood and adolescence do not affect all tracts in the periventricular zone and can involve both decreased and increased FA. Differences in the patterns of radial diffusivity and axial diffusivity suggest that the tissue properties underlying group FA differences may vary within and across white matter tracts. Distinctive diffusion properties may relate to variations in the timing of injury in the neonatal period, extent of white matter dysmaturity and/or compensatory processes in childhood. PMID:26560745

  7. Decreased Amyloid-β Pathologies by Intracerebral Loading of Glycosphingolipid-enriched Exosomes in Alzheimer Model Mice*

    PubMed Central

    Yuyama, Kohei; Sun, Hui; Sakai, Shota; Mitsutake, Susumu; Okada, Megumi; Tahara, Hidetoshi; Furukawa, Jun-ichi; Fujitani, Naoki; Shinohara, Yasuro; Igarashi, Yasuyuki

    2014-01-01

    Elevated levels of amyloid-β peptide (Aβ) in the human brain are linked to the pathogenesis of Alzheimer disease. Recent in vitro studies have demonstrated that extracellular Aβ can bind to exosomes, which are cell-secreted nanovesicles with lipid membranes that are known to transport their cargos intercellularly. Such findings suggest that the exosomes are involved in Aβ metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped Aβ and with the associated Aβ were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid-β precursor protein transgenic mice resulted in marked reductions in Aβ levels, amyloid depositions, and Aβ-mediated synaptotoxicity in the hippocampus. In addition, we determined that glycosphingolipids (GSLs), a group of membrane glycolipids, are highly abundant in the exosomes, and the enriched glycans of the GSLs are essential for Aβ binding and assembly on the exosomes both in vitro and in vivo. Our data demonstrate that intracerebrally administered exosomes can act as potent scavengers for Aβ by carrying it on the exosome surface GSLs and suggest a role of exosomes in Aβ clearance in the central nervous system. Improving Aβ clearance by exosome administration would provide a novel therapeutic intervention for Alzheimer disease. PMID:25037226

  8. Methanolic extract of Piper nigrum fruits improves memory impairment by decreasing brain oxidative stress in amyloid beta(1-42) rat model of Alzheimer's disease.

    PubMed

    Hritcu, Lucian; Noumedem, Jaurès A; Cioanca, Oana; Hancianu, Monica; Kuete, Victor; Mihasan, Marius

    2014-04-01

    The present study analyzed the possible memory-enhancing and antioxidant proprieties of the methanolic extract of Piper nigrum L. fruits (50 and 100 mg/kg, orally, for 21 days) in amyloid beta(1-42) rat model of Alzheimer's disease. The memory-enhancing effects of the plant extract were studied by means of in vivo (Y-maze and radial arm-maze tasks) approaches. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase-, catalase-, glutathione peroxidase-specific activities and the total content of reduced glutathione, malondialdehyde, and protein carbonyl levels. The amyloid beta(1-42)-treated rats exhibited the following: decrease of spontaneous alternations percentage within Y-maze task and increase of working memory and reference memory errors within radial arm-maze task. Administration of the plant extract significantly improved memory performance and exhibited antioxidant potential. Our results suggest that the plant extract ameliorates amyloid beta(1-42)-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus. PMID:24442916

  9. Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy

    PubMed Central

    Roher, Alex E.; Cribbs, David H.; Kim, Ronald C.; Maarouf, Chera L.; Whiteside, Charisse M.; Kokjohn, Tyler A.; Daugs, Ian D.; Head, Elizabeth; Liebsack, Carolyn; Serrano, Geidy; Belden, Christine; Sabbagh, Marwan N.; Beach, Thomas G.

    2013-01-01

    The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline. PMID:23555764

  10. COPS5 Protein Overexpression Increases Amyloid Plaque Burden, Decreases Spinophilin-immunoreactive Puncta, and Exacerbates Learning and Memory Deficits in the Mouse Brain*

    PubMed Central

    Wang, Ruizhi; Wang, Hongjie; Carrera, Ivan; Xu, Shaohua; Lakshmana, Madepalli K.

    2015-01-01

    Brain accumulation of neurotoxic amyloid β (Aβ) peptide because of increased processing of amyloid precursor protein (APP), resulting in loss of synapses and neurodegeneration, is central to the pathogenesis of Alzheimer disease (AD). Therefore, the identification of molecules that regulate Aβ generation and those that cause synaptic damage is crucial for future therapeutic approaches for AD. We demonstrated previously that COPS5 regulates Aβ generation in neuronal cell lines in a RanBP9-dependent manner. Consistent with the data from cell lines, even by 6 months, COPS5 overexpression in APΔE9 mice (APΔE9/COPS5-Tg) significantly increased Aβ40 levels by 32% (p < 0.01) in the cortex and by 28% (p < 0.01) in the hippocampus, whereas the increases for Aβ42 were 37% (p < 0.05) and 34% (p < 0.05), respectively. By 12 months, the increase was even more robust. Aβ40 levels increased by 63% (p < 0.001) in the cortex and by 65% (p < 0.001) in the hippocampus. Similarly, Aβ42 levels were increased by 69% (p < 0.001) in the cortex and by 71% (p < 0.011) in the hippocampus. Increased Aβ levels were translated into an increased amyloid plaque burden both in the cortex (54%, p < 0.01) and hippocampus (64%, p < 0.01). Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPβ and decreased levels of sAPPα. Furthermore, COPS5 overexpression reduced spinophilin in both the cortex (19%, p < 0.05) and the hippocampus (20%, p < 0.05), leading to significant deficits in learning and memory skills. Therefore, like RanBP9, COPS5 also plays a pivotal role in amyloid pathology in vivo. PMID:25713139

  11. Folic acid deficiency enhances abeta accumulation in APP/PS1 mice brain and decreases amyloid-associated miRNAs expression.

    PubMed

    Liu, Huan; Tian, Tian; Qin, Shanchun; Li, Wen; Zhang, Xumei; Wang, Xuan; Gao, Yuxia; Huang, Guowei

    2015-12-01

    Recent efforts have revealed the microRNA (miRNA) pathways in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have revealed an association between folic acid deficiency and AD risk. However, the effects of folic acid deficiency on miRNA expression in AD animals have not been observed. We aimed to find if folic acid deficiency may enhance amyloid-β (Aβ) peptide deposition and regulate amyloid-associated miRNAs and their target genes expression in APP/PS1 mice. APP/PS1 mice and N2a cells were treated with folic acid-deficient diet or medium. Cognitive function of mice was assessed using the Morris water maze. miRNA profile was tested by polymerase chain reaction (PCR) array. Different expressional miRNAs were validated by real-time PCR. The deposition of Aβ plaques was evaluated by immunohistochemistry and enzyme-linked immunosorbent assay. APP and BACE1 proteins in mice brain and N2a cells were determined by Western blot. Folic acid deficiency aggravated amyloid pathology in AD mice. The AD+FD group showed shorter time spent in the target zone during the probe test. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that were differentially modulated by folic acid deficiency. In APP/PS1 mice brains and N2a cells with folic acid-deficient treatment, miR-106a-5p, miR-200b-3p and miR-339-5p were down-regulated, and their target genes APP and BACE1 were up-regulated. In conclusion, folic acid deficiency can enhance Aβ accumulation in APP/PS1 mice brain and decrease amyloid-associated miRNAs expression. PMID:26345540

  12. Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.

    PubMed

    Westwood, Sarah; Leoni, Emanuela; Hye, Abdul; Lynham, Steven; Khondoker, Mizanur R; Ashton, Nicholas J; Kiddle, Steven J; Baird, Alison L; Sainz-Fuertes, Ricardo; Leung, Rufina; Graf, John; Hehir, Cristina Tan; Baker, David; Cereda, Cristina; Bazenet, Chantal; Ward, Malcolm; Thambisetty, Madhav; Lovestone, Simon

    2016-03-29

    Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature. PMID:27031486

  13. Inhalation of coriander volatile oil increased anxiolytic-antidepressant-like behaviors and decreased oxidative status in beta-amyloid (1-42) rat model of Alzheimer's disease.

    PubMed

    Cioanca, Oana; Hritcu, Lucian; Mihasan, Marius; Trifan, Adriana; Hancianu, Monica

    2014-05-28

    The present study analyzed the possible anxiolytic, antidepressant and antioxidant proprieties of inhaled coriander volatile oil extracted from Coriandrum sativum var. microcarpum in beta-amyloid (1-42) rat model of Alzheimer's disease. The anxiolytic- and antidepressant-like effects of inhaled coriander volatile oil were studied by means of in vivo (elevated plus-maze and forced swimming tests) approaches. Also, the antioxidant activity in the hippocampus was assessed using catalase specific activity and the total content of the reduced glutathione. The beta-amyloid (1-42)-treated rats exhibited the following: decrease of the locomotor activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming and immobility times within forced swimming test. Exposure to coriander volatile oil significantly improved these parameters, suggesting anxiolytic- and antidepressant-like effects. Moreover, coriander volatile oil decreased catalase activity and increased glutathione level in the hippocampus. Our results suggest that multiple exposures to coriander volatile oil can be useful as a mean to counteract anxiety, depression and oxidative stress in Alzheimer's disease conditions. PMID:24747275

  14. FLZ Alleviates the Memory Deficits in Transgenic Mouse Model of Alzheimer’s Disease via Decreasing Beta-Amyloid Production and Tau Hyperphosphorylation

    PubMed Central

    Wang, Tao; Kong, Xiang-Chen; Tai, Wen-Jiao; Sun, Hua; Zhang, Dan

    2013-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β-amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ’s neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ’s inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β. PMID:24223757

  15. Significance of decreased serum interleukin-10 levels in the progression of cerebral infarction.

    PubMed

    Diao, Zeng-Yan; Wang, Cui-Lan; Qi, Hong-Shun; Jia, Guo-Yong; Yan, Chuan-Zhu

    2016-05-01

    Anti-inflammatory cytokine and its serological detection may have an important role in the process of cardiovascular and cerebrovascular diseases. We investigated whether serum interleukin-10 (IL-10) is associated with cerebral infarction or not in the general population. Identified comprehensive searching was performed covering PubMed, EMBASE, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine, and China National Knowledge Infrastructure databases. Two reviewers extracted data and assessed studies independently. Information was extracted separately and classed into Asians and Caucasians. Summary standardized mean differences (SMDs) with 95 % confidence intervals (CI) were used with the utilization of Z test. Nine studies ranged from 2003 to 2014 were collected for meta-analysis. Results identified a negative association between serum IL-10 levels and cerebral infarction (SMD = 1.80, 95 % CI 0.79-2.81, P < 0.001). Country-subgroup analysis showed that low IL-10 level may be the main risk factor for cerebral infarction in India (SMD = 1.44, 95 % CI 1.13-1.75, P < 0.001) and Croatia (SMD = 2.96, 95 % CI 2.48-3.44, P < 0.001). In the ethnicity-stratified subgroup analysis, serum IL-10 levels were negatively correlated with cerebral infarction in Asians (SMD = 2.52, 95 % CI 0.47-4.57, P = 0.016), while not in Caucasians (P > 0.05). The lower serum IL-10 concentration was significantly associated with an increased likelihood of cerebral infarction in this meta-analysis. More prospective studies should be conducted to provide stronger evidence justifying the use of IL-10 as new biomarker to identify a predisposition toward cerebral infarction. PMID:25847570

  16. Twin-reversed arterial perfusion sequence associated with decreased fetal cerebral vascular impedance

    PubMed Central

    Peyvandi, S.; Feldstein, V. A.; Hirose, S.; Rand, L.; Brook, M. M.; Moon-Grady, A. J.

    2015-01-01

    Objectives Twin-reversed arterial perfusion (TRAP) sequence affects 1% of monochorionic twin pregnancies and is caused by abnormal vascular connections between a pump twin and an acardiac mass. The effects of abnormal vascular connections on cerebral vasculature in the pump twin are unknown. We hypothesize that abnormal cerebral vascular impedance, as assessed by the pulsatility index (PI), is present in pump twins and that fetal intervention alters cerebral impedance. Methods Fetal echocardiograms performed between 2010 and 2013 in pregnancies diagnosed with TRAP (n = 19), recorded at presentation, and uncomplicated monochorionic twin pregnancies (controls, n = 18; 36 fetuses) were analyzed. In all subjects, the middle cerebral artery (MCA)-PI, combined cardiac output (CCO) and cardiothoracic ratio were calculated, and the values for cases and controls were compared. Results The mean gestational age at the time of echocardiography was 20 weeks in both groups. MCA-PI was lower in TRAP cases than in controls (1.55 (95%CI, 1.47–1.64) vs 1.74 (95% CI, 1.65–1.82), respectively; P = 0.004). CCO in TRAP cases was mildly elevated for gestational age (199.7 (95% CI, 138.4–261.1) mL/min) compared with that of controls (131.4 (95% CI, 102.2–160.7) mL/min). In six TRAP cases with a second echocardiogram available, the mean MCA-PI increased after intervention, from 1.5 (95%CI, 1.3–1.7) to 1.8 (95% CI, 1.4–2.2). Conclusions TRAP pump twins have lower cerebral vascular impedance than do controls, suggestive of a brain-sparing effect. MCA-PI appeared to increase in a small group of pump twins after intervention. These findings suggest a fetal cerebral autoregulatory response to a high cardiac output state that begins to change after fetal intervention. The long-termimplications for neurodevelopmental outcome warrant further study. PMID:25157457

  17. A Human Monoclonal IgG That Binds Aβ Assemblies and Diverse Amyloids Exhibits Anti-Amyloid Activities In Vitro and In Vivo

    PubMed Central

    O'Nuallain, Brian; Puligedda, Rama Devudu; Ondrejcak, Tomas; Adekar, Sharad P.; Chen, Cindy; Cruz, Pedro E.; Rosario, Awilda M.; Macy, Sallie; Mably, Alexandra J.; Walsh, Dominic M.; Vidal, Ruben; Solomon, Alan; Brown, Daniel; Rowan, Michael J.; Golde, Todd E.

    2015-01-01

    Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aβ and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aβ and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aβ in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aβ amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases. PMID:25904780

  18. Computational analysis of pediatric ventricular assist device implantation to decrease cerebral particulate embolization.

    PubMed

    Nguyen, ThuyTien; Argueta-Morales, I Ricardo; Guimond, Stephen; Clark, William; Ceballos, Andres; Osorio, Ruben; Divo, Eduardo A; De Campli, William M; Kassab, Alain J

    2016-01-01

    Stroke is the most devastating complication after ventricular assist device (VAD) implantation with a 19% incidence and 65% mortality in the pediatric population. Current pediatric VAD technology and anticoagulation strategies alone are suboptimal. VAD implantation assisted by computational methods (CFD) may contribute reducing the risk of cerebral embolization. Representative three-dimensional aortic arch models of an infant and a child were generated. An 8 mm VAD outflow-graft (VAD-OG) anastomosed to the aorta was rendered and CFD was applied to study blood flow patterns. Particle tracks, originating in the VAD, were computed with a Lagrangian phase model and the percentage of particles entering the cerebral vessels was calculated. Eight implantation configurations (infant = 5 and child = 3) and 5 particle sizes (0.5, 1, 2, 3, and 4 mm) were considered. For the infant model, percentage of particles entering the cerebral vessels ranged from 15% for a VAD-OG anastomosed at 90° to the aorta, to 31% for 30° VAD-OG anastomosis (overall percentages: X(2) = 10,852, p < 0.0001). For the child model, cerebral embolization ranged from 9% for the 30° VAD-OG anastomosis to 15% for the 60° anastomosis (overall percentages: χ(2) = 10,323, p < 0.0001). Using detailed CFD calculations, we demonstrate that the risk of stroke depends significantly on the VAD implantation geometry. In turn, the risk probably depends on patient-specific anatomy. CFD can be used to optimize VAD implantation geometry to minimize stroke risk. PMID:26214744

  19. Cerebral Blood Flow and Glucose Metabolism Measured With Positron Emission Tomography Are Decreased in Human Type 1 Diabetes

    PubMed Central

    van Golen, Larissa W.; Huisman, Marc C.; Ijzerman, Richard G.; Hoetjes, Nikie J.; Schwarte, Lothar A.; Lammertsma, Adriaan A.; Diamant, Michaela

    2013-01-01

    Subclinical systemic microvascular dysfunction exists in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow (CBF) and metabolism in these patients. We performed dynamic [15O]H2O and [18F]-fluoro-2-deoxy-d-glucose brain positron emission tomography scans to measure CBF and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on coregistered magnetic resonance images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total gray matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic subjects versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, which is only partially explained by the decreased CBF. These findings suggest that mechanisms other than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes. PMID:23530004

  20. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically-verified Alzheimer’s disease

    PubMed Central

    Ringman, John M.; Sachs, Michael C.; Zhou, Yan; Monsell, Sarah E.; Saver, Jeffrey L.; Vinters, Harry V.

    2014-01-01

    Importance Though cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it is limited. Objective We sought to determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically-confirmed Alzheimer’s disease (AD). Design We compared demographic and clinical variables at the earliest visit during life at which subjects were found to have cognitive impairment, and pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and non-carriers of the APOE ε4 allele. Setting Data were obtained from the Uniform Data Set that comprises longitudinal clinical assessments performed in the Alzheimer’s Disease Centers funded by the National Institute on Aging. Participants 193 persons with severe CAA and 232 persons with no CAA. All subjects had cognitive impairment and met NIA-Reagan neuropathological criteria for AD. Main Outcome Measures Prevalence of demographic characteristics and the APOE ε4 allele and odds ratios of clinical variables for the prediction of severe CAA. Results Persons with severe CAA were more likely to carry an APOE ε4 allele (64.9% vs. 42.8%), to be Hispanic (6.8% vs. 1.3%, p = 0.003), to have had a transient ischemic attack (TIA, 12.5% vs. 6.1%, OR = 2.1, 95% CI = 1 – 4.4), and had lower degrees of diffuse amyloid plaque pathology (mean CERAD scores 1.2 vs. 1.4, p = 0.01) than persons with no CAA. Intracerebral hemorrhage (9.3% vs. 3.5%, p = 0.01), cortical microinfarcts (20.7% vs. 12.9%, p = 0.03), and subcortical leukoencephalopathy (20.5% vs. 12.1%, p = 0.02) were more common in persons with CAA. A higher prevalence of stroke (11.1% vs. 3.9%, OR = 3.8, 95% CI 1.0 – 14.6) and hypercholesterolemia (50% vs. 33.3%, OR = 2.3, CI 1.1 – 4.7) were found in non-carriers of the ε4 allele with

  1. Oral administration of synthetic retinoid Am80 (Tamibarotene) decreases brain beta-amyloid peptides in APP23 mice.

    PubMed

    Kawahara, Kohichi; Nishi, Kentaro; Suenobu, Michita; Ohtsuka, Hideyuki; Maeda, Akira; Nagatomo, Kenichiro; Kuniyasu, Akihiko; Staufenbiel, Matthias; Nakagomi, Madoka; Shudo, Koichi; Nakayama, Hitoshi

    2009-07-01

    The purpose of this study is to investigate whether a synthetic retinoid Am80 (tamibarotene) exhibits any improving effects on amyloid precursor protein (APP)23 mice, a model of Alzheimer's disease. Am80 was orally administered in feed to 20-week (5-month)-old APP23 mice at a dose of 0 (control) or 0.5 mg/kg/d for 14 weeks. The Am80 treatment reduced significantly the insoluble Abeta levels in brain, in particular Abeta(42), while it gave no apparent effects on the soluble Abeta levels. The results suggest that oral administration of Am80 may have potency to reduce the extracellular Abeta(42) of insoluble and possibly oligomeric or protofibril forms, which are related to the cause and/or progression of Alzheimer's disease. The Am80 treatment showed no significant effect on spatial learning and memory of APP23 mice by Morris water maze analysis. The main reason for the absence of significance seems based on the large deviation and some mice both in the treated and the non-treated groups would neither swim nor make efforts to reach the platform. PMID:19571405

  2. Alzheimer's disease neurodegenerative biomarkers are associated with decreased cognitive function but not β-amyloid in cognitively normal older individuals.

    PubMed

    Wirth, Miranka; Madison, Cindee M; Rabinovici, Gil D; Oh, Hwamee; Landau, Susan M; Jagust, William J

    2013-03-27

    β-Amyloid (Aβ) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aβ deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aβ burden for brain regions that are most affected in AD. PMID:23536070

  3. β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

    PubMed Central

    Murray, Patrick S.; Kirkwood, Caitlin M.; Gray, Megan C.; Ikonomovic, Milos D.; Paljug, William R.; Abrahamson, Eric E.; Henteleff, Ruth A.; Hamilton, Ronald L.; Kofler, Julia K.; Klunk, William E.; Lopez, Oscar L.; Penzes, Peter; Sweet, Robert A.

    2012-01-01

    Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in AD phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long term potentiation. In contrast, the Rho GEF kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from fifty-two AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid1-42/β-amyloid1-40 ratio was increased, due primarily to reduced soluble β-amyloid1-40, and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid1-42/β-amyloid1-40 ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD. PMID:22429885

  4. Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

    PubMed Central

    Berry, Anne S.; Tomidokoro, Yasushi; Ghiso, Jorge; Thornton, Jan

    2008-01-01

    Numerous studies have suggested that estradiol (E) improves spatial memory as female rats with E perform better than those without E. However there is an inverse relationship between E and luteinizing hormone (LH) levels and LH could play a role. We examined whether treatment with the LH homologue human chorionic gonadotropin (hCG), would impair spatial memory of adult E-treated female rats. In the Object Location Memory Task, ovariectomized (ovxed) rats treated with E and either a single high dose (400IU/kg) or a lower repeated dose of hCG (75 IU/kg hourly for 8 hours) showed spatial memory disruption compared to ovxed rats treated with estradiol alone. Impairment was attributed to memory disruption as performance improved with shortened delay between task exposure and testing. Tests on another spatial memory task, the Barnes maze, confirmed that hCG (400IU/kg) can impair memory: although E + veh treated animals made significantly fewer hole errors across time, E + hCG treated did not. In humans, high LH levels have been correlated with Alzheimer’s Disease (AD). Because brain amyloid-beta (Aβ) species have been implicated as a toxic factor thought to cause memory loss in AD, we analyzed whether hCG-treated animals had increased Aβ levels. Levels of Aβ from whole brains or hippocampi were assessed by Western Blot. hCG treatment to E-implanted females significantly increased soluble Aβ40 and Aβ42 levels. These results indicate that high levels of LH/hCG can impair spatial memory, and an increase in brain Aβ species may account for the memory impairment in hCG-treated rats. PMID:18413150

  5. Cerebral amyloid-β accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies.

    PubMed

    Bird, Sabine M; Sohrabi, Hamid R; Sutton, Thomas A; Weinborn, Michael; Rainey-Smith, Stephanie R; Brown, Belinda; Patterson, Leigh; Taddei, Kevin; Gupta, Veer; Carruthers, Malcolm; Lenzo, Nat; Knuckey, Neville; Bucks, Romola S; Verdile, Giuseppe; Martins, Ralph N

    2016-05-01

    Traumatic brain injury (TBI) increases the risk of neurodegenerative disorders many years post-injury. However, molecular mechanisms underlying the relationship between TBI and neurodegenerative diseases, such as Alzheimer's disease (AD), remain to be elucidated. Nevertheless, previous studies have demonstrated a link between TBI and increased amyloid-β (Aβ), a protein involved in AD pathogenesis. Here, we review animal studies that measured Aβ levels following TBI. In addition, from a pool of initially identified 1209 published papers, we examined data from 19 eligible animal model studies using a meta-analytic approach. We found an acute increase in cerebral Aβ levels ranging from 24h to one month following TBI (overall log OR=2.97±0.40, p<0.001). These findings may contribute to further understanding the relationship between TBI and future dementia risk. The methodological inconsistencies of the studies discussed in this review suggest the need for improved and more standardised data collection and study design, in order to properly elucidate the role of TBI in the expression and accumulation of Aβ. PMID:26899257

  6. Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons.

    PubMed

    SanMartín, C D; Paula-Lima, A C; Hidalgo, C; Núñez, M T

    2012-08-01

    Two major lesions are pathological hallmarks in Alzheimer's disease (AD): the presence of neurofibrillary tangles formed by intracellular aggregates of the hyperphosphorylated form of the cytoskeletal tau protein, and of senile plaques composed of extracellular aggregates of amyloid beta (Aβ) peptide. Current hypotheses regard soluble amyloid beta oligomers (AβOs) as pathological causative agents in AD. These aggregates cause significant calcium deregulation and mediate neurotoxicity by disrupting synaptic activity. Additionally, the presence of high concentrations of metal ions such as copper, zinc, aluminum and iron in neurofibrillary tangles and senile plaques, plus the fact that they accelerate the rate of formation of Aβ fibrils and AβOs in vitro, suggests that accumulation of these metals in the brain is relevant to AD pathology. A common cellular response to AβOs and transition metals such as copper and iron is the generation of oxidative stress, with the ensuing damage to cellular components. Using hippocampal neurons in primary culture, we report here the effects of treatment with AβOs on the (+)IRE and (-)IRE mRNA levels of the divalent metal transporter DMT1. We found that non-lethal AβOs concentrations decreased DMT1 (-)IRE without affecting DMT1 (+)IRE mRNA levels, and inhibited non-transferrin bound iron uptake. In addition, since both iron and AβOs induce oxidative damage, we studied whether their neurotoxic effects are synergistic. In the range of concentrations and times used in this study, AβOs did not potentiate iron-induced cell death while iron chelation did not decrease AβOs-induced cell death. The lack of synergism between iron and AβOs suggests that these two neurotoxic agents converge in a common target, which initiates signaling processes that promote neurodegeneration. PMID:22526560

  7. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia.

    PubMed

    Zhao, Wanhong; Luo, Chao; Wang, Jue; Gong, Jian; Li, Bin; Gong, Yingxia; Wang, Jun; Wang, Hanqin

    2014-04-01

    3-N-butylphthalide is an effective drug for acute ischemic stroke. However, its effects on chronic cerebral ischemia-induced neuronal injury remain poorly understood. Therefore, this study ligated bilateral carotid arteries in 15-month-old rats to simulate chronic cerebral ischemia in aged humans. Aged rats were then intragastrically administered 3-n-butylphthalide. 3-N-butylphthalide administration improved the neuronal morphology in the cerebral cortex and hippocampus of rats with chronic cerebral ischemia, increased choline acetyltransferase activity, and decreased malondialdehyde and amyloid beta levels, and greatly improved cognitive function. These findings suggest that 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby improving cerebral neuronal injury and cognitive deficits. PMID:25206879

  8. A subanesthetic concentration of sevoflurane increases regional cerebral blood flow and regional cerebral blood volume and decreases regional mean transit time and regional cerebrovascular resistance in volunteers.

    PubMed

    Kolbitsch, C; Lorenz, I H; Hörmann, C; Schocke, M; Kremser, C; Zschiegner, F; Löckinger, A; Pfeiffer, K P; Felber, S; Benzer, A

    2000-07-01

    Inhaled anesthetics exert metabolically mediated effects on cerebral blood vessels both directly and indirectly. We investigated the effects of a 0.4 minimum alveolar subanesthetic concentration of sevoflurane on regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional cerebrovascular resistance (rCVR), and regional mean transit time (rMTT) in volunteers by means of contrast-enhanced magnetic resonance imaging perfusion measurement. Sevoflurane increased rCBF by 16% to 55% (control, 55. 03 +/- 0.33 to 148.83 +/- 1.9 mL. 100 g(-1). min(-1); sevoflurane, 71.75 +/- 0.36 to 193.26 +/- 2.14 mL. 100 g(-1). min(-1)) and rCBV by 7% to 39% (control, 4.66 +/- 0.03 to 10.04 +/- 0.12 mL/100 g; sevoflurane, 5.04 +/- 0.03 to 13.6 +/- 0.15 mL/100 g); however, sevoflurane decreased rMTT by 7% to 18% (control, 3.75 +/- 0.04 to 5. 39 +/- 0.04 s; sevoflurane, 3.4 +/- 0.03 to 4.44 +/- 0.03 s) and rCVR by 22% to 36% (control, 0.74 +/- 0.01 to 1.9 +/- 0.2 mm Hg/[mL. 100 g(-1). min(-1)]; sevoflurane, 0.54 +/- 0.01 to 1.41 +/- 0.01 mm Hg/[mL. 100 g(-1). min(-1)]). Interhemispheric differences in rCBF, rCBV, and rCVR were markedly reduced after the administration of sevoflurane. These findings are consistent with the known direct vasodilating effect of sevoflurane. The decrease in rMTT further shows that rCBF increases more than does rCBV. Furthermore, we can show that the observed increase in rCBF during inhalation of sevoflurane is not explained by vasodilation alone. PMID:10866904

  9. Middle cerebral O2 delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine

    PubMed Central

    Medow, Marvin S.; DelPozzi, Andrew; Messer, Zachary R.; Terilli, Courtney; Schwartz, Christopher E.

    2013-01-01

    The modified Oxford maneuver is the reference standard for assessing arterial baroreflex function. The maneuver comprises a systemic bolus injection of 100 μg sodium nitroprusside (SNP) followed by 150 μg phenylephrine (PE). On the one hand, this results in an increase in oxyhemoglobin and total hemoglobin followed by a decrease within the cerebral sample volume illuminated by near-infrared spectroscopy (NIRS). On the other hand, it produces a decrease in cerebral blood flow velocity (CBFv) within the middle cerebral artery (MCA) during SNP and an increase in CBFv during PE as measured by transcranial Doppler ultrasound. To resolve this apparent discrepancy, we hypothesized that SNP dilates, whereas PE constricts, the MCA. We combined transcranial Doppler ultrasound of the right MCA with NIRS illuminating the right frontal cortex in 12 supine healthy subjects 18–24 yr old. Assuming constant O2 consumption and venous saturation, as estimated by partial venous occlusion plethysmography, we used conservation of mass (continuity) equations to estimate the changes in arterial inflow (ΔQa) and venous outflow (ΔQv) of the NIRS-illuminated area. Oxyhemoglobin and total hemoglobin, respectively, increased by 13.6 ± 1.6 and 15.2 ± 1.4 μmol/kg brain tissue with SNP despite hypotension and decreased by 6 ± 1 and 7 ± 1 μmol/kg with PE despite hypertension. SNP increased ΔQa by 0.36 ± .03 μmol·kg−1·s−1 (21.6 μmol·kg−1·min−1), whereas CBFv decreased from 71 ± 2 to 62 ± 2 cm/s. PE decreased ΔQa by 0.27 ± .2 μmol·kg−1·s−1 (16.2 μmol·kg−1·min−1), whereas CBFv increased to 75 ± 3 cm/s. These results are consistent with dilation of the MCA by SNP and constriction by PE. PMID:23564308

  10. Decreased norepinephrine (NE) uptake in cerebral cortex and inferior colliculus of genetically epilepsy prone (GEP) rats

    SciTech Connect

    Browning, R.A.; Rigler-Daugherty, S.K.; Long, G.; Jobe, P.C.; Wade, D.R.

    1986-03-01

    GEP rats are characterized by an enhanced susceptibility to seizures caused by a variety of stimuli, most notably sound. Pharmacological treatments that reduce the synaptic concentration of NE increase seizure severity in GEP rats while elevations in NE have the opposite effect. GEP rats also display a widespread deficit in brain NE concentration suggesting that their increased seizure susceptibility is related to a deficit in noradrenergic transmission. The authors have compared the kinetics of /sup 3/H-NE uptake in the P/sub 2/ synaptosomal fraction isolated from the cerebral cortex of normal and GEP-rats. Although the apparent Kms were not significantly different (Normal +/- SEM:0.37 +/- 0.13..mu..M; GEP +/- SEM: 0.29 +/- 0.07..mu..M), the Vmax for GEP rats was 48% lower than that of normal rats (Normal +/- SEM: 474 +/- 45 fmole/mg/4min; GEP +/- SEM: 248 +/- 16 fmole/mg/4min). Because of the possible role of the inferior colliculus (IC) in the initiation of sound-induced seizures in GEP rats, the authors measured synaptosomal NE uptake in the IC using a NE concentration of 50 nM. The IC synaptosomal NE uptake was found to be 35% lower in GEP than in normal rats. These findings are consistent with the hypothesis that a deficit in noradrenergic transmission is related to the increased seizure susceptibility of GEP rats.

  11. Is perivetricular hyperintensity region caused by decreased cerebral blood flow?; assessment by {sup 15}O-PET study

    SciTech Connect

    Kaminaga, T.; Hayashida, K.; Ishida, Y.

    1994-05-01

    The clinical significance of the regional cerebral blood flow (rCBF) and oxygen metabolism has not been established in patients who had periventricular hyperintensity (PVH) by magnetic resonance imaging (MRI). The aim of this study is to correlate the results of rCBF and oxygen metabolism by positron emission tomography (PET) with PVH by MRI. The subjects were 27 patients; 16 patient (group I) (male; 7, female; 9, age; 56.8{plus_minus}18.6) with PVH and age matched 11 patients (group II) (male; 6, female; 5, age; 55.3{plus_minus}13.6) without PVH. {sup 15}O-PET study was carried out by Headtome IV and rCBF, cerebral metabolic rate of oxygen (CMRO{sub 2}), oxygen extraction fraction (OEF) of PVH and cerebellum was calculated. T1- and T2-weighted images were obtained in all patients. Angiography was performed over 11 patients. The mean rCBF of group I in PVH (28.5{plus_minus}7.5 ml/100g/min) was significantly (p<0.01) lower than that of group II (38.6{plus_minus}5.7). The mean rCBF of group I and group II in cerebellum were 49.5{plus_minus}9.9 ml/100g/min and 50.2{plus_minus}8.9 respectively. There was no significant difference on CMRO{sub 2} and OEF between group I and group II. In MRI examination, PVH was detected in all group I patients and multiple high intensities were also detected in 7 patients of group I and 4 patients of group II on T2-weighted images. No significant stenosis (more than 75%) was detected in 11 patients by angiography. These data strongly indicate that PVH might be caused by decreased cerebral blood flow.

  12. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue

    PubMed Central

    Love, Seth; Chalmers, Katy; Ince, Paul; Esiri, Margaret; Attems, Johannes; Kalaria, Raj; Jellinger, Kurt; Yamada, Masahito; McCarron, Mark; Minett, Thais; Matthews, Fiona; Greenberg, Steven; Mann, David; Kehoe, Patrick Gavin

    2015-01-01

    In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter-rater reliability was demonstrated. Stage two used the results of the three-centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE ε4 was confirmed. However APOE ε2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non-demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA. PMID:26807344

  13. What is normal in normal aging? Effects of Aging, Amyloid and Alzheimer’s Disease on the Cerebral Cortex and the Hippocampus

    PubMed Central

    Fjell, Anders M.; McEvoy, Linda; Holland, Dominic; Dale, Anders M.; Walhovd, Kristine B

    2015-01-01

    What can be expected in normal aging, and where does normal aging stop and pathological neurodegeneration begin? With the slow progression of age-related dementias such as Alzheimer’s Disease (AD), it is difficult to distinguish age-related changes from effects of undetected disease. We review recent research on changes of the cerebral cortex and the hippocampus in aging and the borders between normal aging and AD. We argue that prominent cortical reductions are evident in fronto-temporal regions in elderly even with low probability of AD, including regions overlapping the default mode network. Importantly, these regions show high levels of amyloid deposition in AD, and are both structurally and functionally vulnerable early in the disease. This normalcy-pathology homology is critical to understand, since aging itself is the major risk factor for sporadic AD. Thus, rather than necessarily reflecting early signs of disease, these changes may be part of normal aging, and may inform on why the aging brain is so much more susceptible to AD than is the younger brain. We suggest that regions characterized by a high degree of life-long plasticity are vulnerable to detrimental effects of normal aging, and that this age-vulnerability renders them more susceptible to additional, pathological AD-related changes. We conclude that it will be difficult to understand AD without understanding why it preferably affects older brains, and that we need a model that accounts for age-related changes in AD-vulnerable regions independently of AD-pathology. PMID:24548606

  14. The Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibitor CI-1011 Reverses Diffuse Brain Amyloid Pathology in Aged Amyloid Precursor Protein Transgenic Mice

    PubMed Central

    Huttunen, Henri J.; Havas, Daniel; Peach, Camilla; Barren, Cory; Duller, Stephan; Xia, Weiming; Frosch, Matthew P.; Hutter-Paier, Birgit; Windisch, Manfred; Kovacs, Dora M.

    2010-01-01

    Cerebral accumulation of amyloid β-peptide (Aβ) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) hAPP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Aβ40 and Aβ42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S+ dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in hAPP mice by limiting generation and increasing clearance of diffusible Aβ. PMID:20613640

  15. Inverted optical intrinsic response accompanied by decreased cerebral blood flow are related to both neuronal inhibition and excitation

    PubMed Central

    Ma, Zengguang; Cao, Pengjia; Sun, Pengcheng; Zhao, Linna; Li, Liming; Tong, Shanbao; Lu, Yiliang; Yan, Yan; Chen, Yao; Chai, Xinyu

    2016-01-01

    Negative hemodynamic response has been widely reported in blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging studies, however its origin is still controversial. Optical intrinsic signal (OIS) imaging can be used to study brain activity by simultaneously recording hemodynamic signals at different wavelengths with high spatial resolution. In this study, we found transcorneal electrical stimulation (TcES) could elicit both positive OIS response (POR) and negative OIS response (NOR) in cats’ visual cortex. We then investigated the property of this negative response to TcES and its relationship with cerebral blood flow (CBF) and neuronal activity. Results from laser speckle contrast imaging showed decreased CBF in the NOR region while increased CBF in the POR region. Both planar and laminar electrophysiological recordings in the middle (500–700 μm) cortical layers demonstrated that decreased and increased neuronal activities were coexisted in the NOR region. Furthermore, decreased neuronal activity was also detected in the deep cortical layers in the NOR region. This work provides evidence that the negative OIS together with the decreased CBF should be explained by mechanisms of both neuronal inhibition and excitation within middle cortical layers. Our results would be important for interpreting neurophysiological mechanisms underlying the negative BOLD signals. PMID:26860040

  16. Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow

    PubMed Central

    Xiong, Guoxiang; Elkind, Jaclynn A.; Kundu, Suhali; Smith, Colin J.; Antunes, Marcelo B.; Tamashiro, Edwin; Kofonow, Jennifer M.; Mitala, Christina. M.; Stein, Sherman C.; Grady, M. Sean; Einhorn, Eugene; Cohen, Noam A.

    2014-01-01

    Abstract Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle. PMID:24749541

  17. Cerebral Oedema, Blood-Brain Barrier Breakdown and the Decrease in Na(+),K(+)-ATPase Activity in the Cerebral Cortex and Hippocampus are Prevented by Dexamethasone in an Animal Model of Maple Syrup Urine Disease.

    PubMed

    Rosa, Luciana; Galant, Leticia S; Dall'Igna, Dhébora M; Kolling, Janaina; Siebert, Cassiana; Schuck, Patrícia F; Ferreira, Gustavo C; Wyse, Angela T S; Dal-Pizzol, Felipe; Scaini, Giselli; Streck, Emilio L

    2016-08-01

    Maple syrup urine disease (MSUD) is a rare metabolic disorder associated with acute and chronic brain dysfunction. This condition has been shown to lead to macroscopic cerebral alterations that are visible on imaging studies. Cerebral oedema is widely considered to be detrimental for MSUD patients; however, the mechanisms involved are still poorly understood. Therefore, we investigated whether acute administration of branched-chain amino acids (BCAA) causes cerebral oedema, modifies the Na(+),K(+)-ATPase activity, affects the permeability of the blood-brain barrier (BBB) and alters the levels of cytokines in the hippocampus and cerebral cortex of 10-day-old rats. Additionally, we investigated the influence of concomitant administration of dexamethasone on the alterations caused by BCAA. Our results showed that the animals submitted to the model of MSUD exhibited an increase in the brain water content, both in the cerebral cortex and in the hippocampus. By investigating the mechanism of cerebral oedema, we discovered an association between H-BCAA and the Na(+),K(+)-ATPase activity and the permeability of the BBB to small molecules. Moreover, the H-BCAA administration increases Il-1β, IL-6 and TNF-α levels in the hippocampus and cerebral cortex, whereas IL-10 levels were decreased in the hippocampus. Interestingly, we showed that the administration of dexamethasone successfully reduced cerebral oedema, preventing the inhibition of Na(+),K(+)-ATPase activity, BBB breakdown and the increase in the cytokines levels. In conclusion, these findings suggest that dexamethasone can improve the acute cerebral oedema and brain injury associated with high levels of BCAA, either through a direct effect on brain capillary Na(+),K(+)-ATPase or through a generalized effect on the permeability of the BBB to all compounds. PMID:26133302

  18. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.

    PubMed

    Yuan, Peng; Condello, Carlo; Keene, C Dirk; Wang, Yaming; Bird, Thomas D; Paul, Steven M; Luo, Wenjie; Colonna, Marco; Baddeley, David; Grutzendler, Jaime

    2016-05-18

    Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD. PMID:27196974

  19. Transthyretin stabilization by iododiflunisal promotes amyloid-β peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model.

    PubMed

    Ribeiro, Carlos A; Oliveira, Sandra Marisa; Guido, Luis F; Magalhães, Ana; Valencia, Gregorio; Arsequell, Gemma; Saraiva, Maria João; Cardoso, Isabel

    2014-01-01

    Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease. PMID:24169237

  20. β-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation

    PubMed Central

    Cai, Yan; Xiong, Kun; Zhang, Xue-Mei; Cai, Huaibin; Luo, Xue-Gang; Feng, Jia-Chun; Clough, Richard W.; Struble, Robert G.; Patrylo, Peter R.; Chu, Yaping; Kordower, Jeffrey H.; Yan, Xiao-Xin

    2010-01-01

    Alzheimer's disease (AD) is the most common dementia-causing disorder in the elderly, which may relate to multiple risk factors and is pathologically featured by cerebral hypometabolism, paravascular β-amyloid (Aβ) plaques, neuritic dystrophy and intra-neuronal aggregation of phosphorylated-tau. To explore potential pathogenic link among some of these lesions, we examined β-secretase-1 (BACE1) alteration relative to Aβ deposition, neuritic pathology and vascular organization in aged monkey and AD human cerebral cortex. Western blot analyses detected increased levels of BACE1 proteins and β-site-cleavage amyloid precursor protein C-terminal fragments in plaque-bearing human and monkey cortex relative to controls. In immunohistochemistry, locally elevated BACE1 immunoreactivity (IR) occurred in AD but not in control human cortex, with a trend of increased overall density among cases with greater plaque pathology. In double labeling preparations, BACE1 IR colocalized with immunolabeling for Aβ but not for phosphorylated tau. In perfusion-fixed monkey cortex, locally increased BACE1 IR co-existed with intra-axonal and extracellular Aβ IR among virtually all neuritic plaques ranging from primitive to typical cored forms. This BACE1 labeling localized to swollen/sprouting axon terminals that might co-express one or another neuronal phenotype marker (GABAergic, glutamatergic, cholinergic or catecholaminergic). Importantly, these BACE1-labeled dystrophic axons resided near or in direct contact with blood vessels. These finds implicate that plaque formation in AD or normal aging primates relate to a multisystem axonal pathogenesis that occurs in partnership with potential vascular or metabolic deficit. The data provide a tangible mechanistic explanation as to why senile plaques are present preferentially near cerebral vasculature. PMID:20726888

  1. Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo

    PubMed Central

    Millar, David J.; Richard-Londt, Angela

    2016-01-01

    Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming ‘Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)’ clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA. PMID:26842068

  2. Evaluation of near infrared spectroscopy for detecting the β blocker-induced decrease in cerebral oxygenation during hemodilution in a swine model.

    PubMed

    Kurita, Tadayoshi; Morita, Koji; Sato, Shigehito

    2015-12-01

    β blockers reduce cerebral oxygenation after acute hemodilution and may contribute to the incidence of stroke when used perioperatively. The goal of the study was to investigate whether cerebral tissue oxygenation using near infrared spectroscopy can detect the β blocker-induced decrease in cerebral oxygenation depending on the severity of hemodilution and/or the dose of β blockers. Animals were anesthetized with 2% isoflurane and randomly assigned to a landiolol or esmolol group. After baseline measurement, landiolol or esmolol was administered at 40 µg/kg/min for 20 min, increased to 200 µg/kg/min for 20 min, and then stopped. Hemodynamic and arterial variables and the tissue oxygenation index (TOI) were recorded at each β blocker dose. Two stages of hemodilution were sequentially induced by repeated hemorrhage of 600 ml (33% of estimated blood volume) and infusion of the same volume of hydroxyethylstarch. During each stage, landiolol or esmolol was similarly administered and measurements were made. Landiolol and esmolol both dose-dependently decreased heart rate, mean arterial pressure and cardiac output, depending on the severity of hemodilution. Landiolol at 40 µg/kg/min was almost equivalent in potency to 200 µg/kg/min esmolol for decreasing HR before hemodilution. Based on the TOI, short-acting β blockers reduced cerebral oxygenation in a dose-dependent manner during hemodilution, and oxygenation returned to the baseline level after drug infusion was stopped. TOI may be useful for identification of a decrease in cerebral oxygenation for patients receiving β blockade during surgery associated with major bleeding. PMID:25876017

  3. Neuritic Plaques and Cerebrovascular Amyloid in Alzheimer Disease are Antigenically Related

    NASA Astrophysics Data System (ADS)

    Wong, Caine W.; Quaranta, Vito; Glenner, George G.

    1985-12-01

    A synthetic peptide (Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr), homologous to the amino terminus of a protein purified from cerebrovascular amyloid (β protein), induced antibodies in BALB/c mice that were used immunohistochemically to stain not only amyloid-laden cerebral vessels but neuritic plaques as well. These findings suggest that the amyloid in neuritic plaques shares antigenic determinants with β protein of cerebral vessels. Since the amino acid compositions of plaque amyloid and cerebrovascular amyloid are similar, it is likely that plaque amyloid also consists of β protein. This possibility suggests a model for the pathogenesis of Alzheimer disease involving β protein.

  4. Transmissible amyloid.

    PubMed

    Tjernberg, L O; Rising, A; Johansson, J; Jaudzems, K; Westermark, P

    2016-08-01

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. PMID:27002185

  5. Decreased expression of transient receptor potential channels in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage.

    PubMed

    Thilo, Florian; Suess, Olaf; Liu, Ying; Tepel, Martin

    2011-01-01

    Recent data indicate that transient receptor potential (TRP) cation channels play an important role in hypertension. Now, we tested the hypothesis that TRP expression is altered in human cerebral vascular tissue in patients who had experienced hypertensive intracerebral hemorrhage. TRPC1, TRPC3, TRPC5, TRPC6, TRPM4, TRPM6, and TRPM7 channels were detected in cerebral vascular tissue by quantitative real-time RT-PCR. Control cerebral vascular tissue was obtained from normotensive patients who underwent neurosurgical operation because of brain tumor. To examine a possible relation between the expression of TRP expression and hypoxic conditions caused by the intracerebral bleeding, we examined the expression of hypoxia inducible factor 1a (HIF1a). Transcripts of TRPC3, TRPC5, TRPM6, and HIF1a were significantly reduced in cerebral vascular tissue from patients after hypertensive intracerebral hemorrhage compared to controls. TRPC3 mRNA correlated well with the expression of HIF1a mRNA (r(2) = 0.59; p = 0.01). TRPC3 expression is associated with hypertension and hypoxic conditions in human cerebral vascular tissue. PMID:21957871

  6. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P.

    PubMed Central

    Kowall, N W; Beal, M F; Busciglio, J; Duffy, L K; Yankner, B A

    1991-01-01

    Deposition of the beta-amyloid protein in senile plaques is a pathologic hallmark of Alzheimer disease (AD). Focal deposition of beta amyloid in the adult rat cerebral cortex caused profound neurodegenerative changes, including neuronal loss and degenerating neurons and neurites. Chronic induction of the Alz-50 antigen appeared in neurons around focal cortical deposits of beta amyloid. Immunoblot analysis showed that beta amyloid induced Alz-50-immunoreactive proteins in rat cerebral cortex that were very similar to the proteins induced in human cerebral cortex from patients with AD. The neuropeptide substance P prevented beta-amyloid-induced neuronal loss and expression of Alz-50 proteins when coadministered into the cerebral cortex. Systemic administration of substance P also provided protection against the effects of intracerebral beta amyloid. Thus, beta amyloid is a potent neurotoxin in the adult brain in vivo, and its effects can be blocked by substance P. Images PMID:1714596

  7. Ischemic Postconditioning Decreases Cerebral Edema and Brain Blood Barrier Disruption Caused by Relief of Carotid Stenosis in a Rat Model of Cerebral Hypoperfusion

    PubMed Central

    Yang, Fuwei; Zhang, Xiaojie; Sun, Ying; Wang, Boyu; Zhou, Chuibing; Luo, Yinan; Ge, Pengfei

    2013-01-01

    Background and Purpose Complications due to brain edema and breakdown of blood brain barrier are an important factor affecting the treatment effects of patients with severe carotid stenosis. In this study, we investigated the protective effects of ischemic postconditioning on brain edema and disruption of blood brain barrier via establishing rat model of hypoperfusion due to severe carotid stenosis. Methods Wistar rat model of hypoperfusion due to severe carotid stenosis was established by binding a stainless microtube to both carotid arteries. Ischemic postconditioning procedure consisted of three cycles of 30 seconds ischemia and 30 seconds reperfusion. Brain edema was evaluated by measuring cerebral water content, and blood brain barrier permeability was assayed by examining cerebral concentration of Evans' Blue (EB) and fluorescein sodium (NaF). ELISA was used to analyze the expression of MMP-9, claudin-5 and occludin. The activity and location of MMP-9 was analyzed by gelatin zymography and in situ zymography, respectively. The distribution of tight junction proteins claudin-5 and occludin was observed by immunohistochemistry. Results The increased brain water content and cerebral concentration of EB and NaF were suppressed by administration of ischemic postconditioning prior to relief of carotid stenosis. Zymographic studies showed that MMP-9 was mainly located in the cortex and its activity was significantly improved by relief of carotid stenosis and, but the elevated MMP-9 activity was inhibited markedly by ischemic postconditioning. Immunohistochemistry revealed that ischemic postconditioning improved the discontinuous distribution of claudin-5 and occludin. ELISA detected that the expression of up-regulated MMP-9 and down-regulated claudin-5 and occludin caused by carotid relief were all attenuated by ischemic postconditioning. Conclusions Ischemic postconditioning is an effective method to prevent brain edema and improve BBB permeability and could be

  8. Effect of r-TMS over standard therapy in decreasing muscle tone of spastic cerebral palsy patients.

    PubMed

    Gupta, Meena; Lal Rajak, Bablu; Bhatia, Dinesh; Mukherjee, Arun

    2016-05-01

    Spastic cerebral palsy (CP) is the one of most common neurological disorders occurring due to damage to the immature brain or any other brain lesion at the time of birth. To aid in making the life of the CP patient meaningful, several interventions such as medical, surgical and rehabilitation have been employed to date. Besides these, recently repetitive Transcranial magnetic stimulation (r-TMS) is a new found approach which is being employed for treating various neurological and psychological conditions. The aim of this study was to observe the effects of r-TMS on muscle spasticity in CP patients by stimulating the motor cortex area of the brain, which is responsible for muscle movements. In this study, 20 subjects diagnosed with CP were recruited and 10 each were placed in two groups, namely the research group (RG) (mean age, height and weight were 7.99 (SD = 4.66) years, 116.7 (SD = 23.57) cm and 21.40 (SD = 10.95) kg, respectively) and the control group (CG) (mean age, height and weight were 8.41 (SD = 4.32) years, 107.9 (SD = 26.33) cm, 21.40 (SD = 12.63) kg, respectively). r-TMS frequencies of 5 Hz and 10 Hz were administered for 15 min daily to patients in RG followed by standard therapy (ST) of 1 h duration daily for 20 days. Moreover, the patients in the control group (CG) were given only standard therapy (ST) of 1 h duration for 20 days. Modified Ashworth Scale (MAS) was used as an outcome measure to determine the level of muscle spasticity. A pre- assessment of MAS score was performed on both RG and CG to determine the level of spasticity prior to starting therapy; and similarly post-assessment after 20 days was done to observe the changes post-therapy. Statistical analysis of pre vs post MAS scores showed that few muscles showed reduction in muscle tightness after administering only ST in the CG. On the contrary, the RG that underwent r-TMS therapy combined with ST showed a significant decrease (p < 0.05) in muscle tightness for all the

  9. Amyloid fibrils

    PubMed Central

    Rambaran, Roma N

    2008-01-01

    Amyloid refers to the abnormal fibrous, extracellular, proteinaceous deposits found in organs and tissues. Amyloid is insoluble and is structurally dominated by β-sheet structure. Unlike other fibrous proteins it does not commonly have a structural, supportive or motility role but is associated with the pathology seen in a range of diseases known as the amyloidoses. These diseases include Alzheimer's, the spongiform encephalopathies and type II diabetes, all of which are progressive disorders with associated high morbidity and mortality. Not surprisingly, research into the physicochemical properties of amyloid and its formation is currently intensely pursued. In this chapter we will highlight the key scientific findings and discuss how the stability of amyloid fibrils impacts on bionanotechnology. PMID:19158505

  10. Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice.

    PubMed

    Kumar, V B; Farr, S A; Flood, J F; Kamlesh, V; Franko, M; Banks, W A; Morley, J E

    2000-12-01

    beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory. PMID:11150636

  11. Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

    SciTech Connect

    Komatsu, K.; Takada, G.; Uemura, K.; Shishido, F.; Kanno, I. )

    1990-09-01

    We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using {sup 18}F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity.

  12. Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism

    PubMed Central

    Muratore, Christina R.; Hodgson, Nathaniel W.; Trivedi, Malav S.; Abdolmaleky, Hamid M.; Persico, Antonio M.; Lintas, Carla; De La Monte, Suzanne; Deth, Richard C.

    2013-01-01

    The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-α, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression. PMID:23437274

  13. Plasma β-amyloid in Alzheimer's disease and vascular disease.

    PubMed

    Janelidze, Shorena; Stomrud, Erik; Palmqvist, Sebastian; Zetterberg, Henrik; van Westen, Danielle; Jeromin, Andreas; Song, Linan; Hanlon, David; Tan Hehir, Cristina A; Baker, David; Blennow, Kaj; Hansson, Oskar

    2016-01-01

    Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease. PMID:27241045

  14. Is amyloid beta-protein glycated in Alzheimer's disease?

    PubMed

    Tabaton, M; Perry, G; Smith, M; Vitek, M; Angelini, G; Dapino, D; Garibaldi, S; Zaccheo, D; Odetti, P

    1997-03-01

    Recent data suggest that protein glycation is involved in the process of amyloid formation in Alzheimer's disease (AD). To further investigate this issue, we analyzed the presence of advanced glycation end products (AGE) in soluble and insoluble forms of amyloid beta-protein (A beta) as well as in apolipoprotein E (apoE), a protein bound to amyloid deposits. Both proteins were extracted from cerebral cortex obtained from patients with AD and probed by immunoblotting with two antibodies specific for different AGE, already known to immunocytochemically label amyloid plaques. All the AGE antibodies failed to recognize either A beta or apoE, whereas they reacted with synthetic A beta glycated in vitro. These findings indicate that other proteins associated with amyloid deposits are candidates to be modified with AGE in Alzheimer's cerebral tissue. PMID:9141062

  15. Severe chronic cerebral hypoperfusion induces microglial dysfunction leading to memory loss in APPswe/PS1 mice

    PubMed Central

    Bordeleau, Maude; ElAli, Ayman; Rivest, Serge

    2016-01-01

    Cerebral vasculature plays a key role in controlling brain homeostasis. Cerebral vasculature dysfunction, associated to irregularities in cerebral blood perfusion, has been proposed to directly contribute to Alzheimer's disease (AD) pathogenesis. More precisely, chronic cerebral hypoperfusion, which impairs brain homeostasis, was demonstrated to take place even before cognitive decline. However, the mechanisms underlying the implication of chronic cerebral hypoperfusion in AD pathogenesis remain elusive. Therefore, this study aims at investigating the role of severe chronic cerebral hypoperfusion (SCCH) in AD pathogenesis. For this purpose, SCCH was induced in young APPswe/PS1 in order to evaluate the progression of AD-like pathology in these mice. We observed that SCCH accelerated the cognitive decline of young APPswe/PS1 mice, which was associated with an increased amyloid plaque number in brain parenchyma. In addition, SCCH reduced the activity of extracellular signal-regulated kinases 1/2 (ERK1/2), which has been shown to play an important role in the adaptive responses of neurons. Importantly, SCCH impaired the function of microglial cells, which are implicated in amyloid-β (Aβ) elimination. In vitro approaches underlined the ability of a low-glucose microenvironment to decrease the general activity and phagocytic capacity of microglia. By using a new model of SCCH, our study unravels new insights into the implication of severe chronic cerebral hypoperfusion in AD pathogenesis, mainly by altering microglial cell activity and consequently Aβ clearance. PMID:26918610

  16. ABCG2 is up-regulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Aβ1-40 peptides

    PubMed Central

    Xiong, Huaqi; Callaghan, Debbie; Jones, Aimee; Bai, Jianying; Rasquinha, Ingrid; Smith, Catherine; Pei, Ke; Walker, Douglas; Lue, Lih-Fen; Stanimirovic, Danica; Zhang, Wandong

    2009-01-01

    Alzheimer's disease (AD) is characterized by accumulation and deposition of Aβ peptides in the brain. Aβ deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Aβ can be transported across blood-brain barrier (BBB), aberrant Aβ trafficking across BBB may contribute to Aβ accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly up-regulated in the brains of AD/CAA compared to age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. Aβ alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Aβ-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and co-immunoprecipitated with Aβ. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Aβ1-40 with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Aβ transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Aβ1-40 or scrambled Aβ40-1. Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Aβ in their brains than wt mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood Aβ from entering into brain. ABCG2 up-regulation may serve as a biomarker of CAA vascular pathology in AD patients. PMID:19403814

  17. Urinary kallidinogenase for the treatment of cerebral arterial stenosis

    PubMed Central

    Zhao, Liandong; Zhao, Ying; Wan, Qi; Zhang, Haijun

    2015-01-01

    Aim Urinary kallidinogenase (UK) has shown promise in improving cerebral perfusion. This study aimed to examine how UK affects cognitive status and serum levels of amyloid betas (Aβs) 1-40 and 1-42 in patients with cerebral arterial stenosis. Methods Ninety patients with cerebral arterial stenosis were enrolled, of whom 45 patients received UK + conventional treatment (UK group), and 45 patients received conventional treatment alone as control group. Cognitive status and Aβ1-40 and Aβ1-42 serum levels were determined before treatment and at 4 weeks and 8 weeks after treatment. Results At 4 weeks after treatment, cognitive status in patients treated with UK clearly improved accompanied by Aβ1-40 serum levels decreasing while there was no change of Aβ1-42. Cognitive status in patients receiving UK continued to improve, Aβ1-40 serum levels declined further as well as Aβ1-42 serum levels began to decrease dramatically at 8 weeks after treatment. Conclusion UK could improve cognitive status and decrease both Aβ1-40 and Aβ1-42 serum levels to prevent ischemic cerebral injury, which represents a good option for patients with cerebral arterial stenosis. PMID:26508834

  18. Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study

    PubMed Central

    Lerch, Jason; Furukawa, Yoshiaki; Tong, Junchao; McCluskey, Tina; Wilkins, Diana; Houle, Sylvain; Meyer, Jeffrey; Mundo, Emanuela; Wilson, Alan A.; Rusjan, Pablo M.; Saint-Cyr, Jean A.; Guttman, Mark; Collins, D. Louis; Shapiro, Colin; Warsh, Jerry J.; Boileau, Isabelle

    2010-01-01

    Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [11C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range –19 to –46%) and hippocampus (–21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self

  19. Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to {beta}-amyloid

    SciTech Connect

    Magrane, Jordi; Christensen, Rial A.; Rosen, Kenneth M.; Veereshwarayya, Vimal; Querfurth, Henry W. . E-mail: hquerf01@granite.tufts.edu

    2006-04-15

    Cerebrovascular deposits of {beta}-amyloid (A{beta}) peptides are found in Alzheimer's disease and cerebral amyloid angiopathy with stroke or dementia. Dysregulations of angiogenesis, the blood-brain barrier and other critical endothelial cell (EC) functions have been implicated in aggravating chronic hypoperfusion in AD brain. We have used cultured ECs to model the effects of {beta}-amyloid on the activated phosphorylation states of multifunctional serine/threonine kinases since these are differentially involved in the survival, proliferation and migration aspects of angiogenesis. Serum-starved EC cultures containing amyloid-{beta} peptides underwent a 2- to 3-fold increase in nuclear pyknosis. Under growth conditions with sublethal doses of {beta}-amyloid, loss of cell membrane integrity and inhibition of cell proliferation were observed. By contrast, cell migration was the most sensitive to A{beta} since inhibition was significant already at 1 {mu}M (P = 0.01, migration vs. proliferation). In previous work, intracellular A{beta} accumulation was shown toxic to ECs and Akt function. Here, extracellular A{beta} peptides do not alter Akt activation, resulting instead in proportionate decreases in the phosphorylations of the MAPKs: ERK1/2 and p38 (starting at 1 {mu}M). This inhibitory action occurs proximal to MEK1/2 activation, possibly through interference with growth factor receptor coupling. Levels of phospho-JNK remained unchanged. Addition of PD98059, but not LY294002, resulted in a similar decrease in activated ERK1/2 levels and inhibition of EC migration. Transfection of ERK1/2 into A{beta}-poisoned ECs functionally rescued migration. The marked effect of extracellular A{beta} on the migration component of angiogenesis is associated with inhibition of MAPK signaling, while Akt-dependent cell survival appears more affected by cellular A{beta}.

  20. Pentylenetetrazol-induced seizures are associated with Na⁺,K⁺-ATPase activity decrease and alpha subunit phosphorylation state in the mice cerebral cortex.

    PubMed

    Marquezan, Bárbara P; Funck, Vinícius R; Oliveira, Clarissa V; Pereira, Letícia M; Araújo, Stífani M; Zarzecki, Micheli S; Royes, Luiz Fernando F; Furian, Ana Flávia; Oliveira, Mauro S

    2013-08-01

    The present study aimed to investigate whether Na(+),K(+)-ATPase activity and phosphorylation state of the catalytic α subunit are altered by pentylenetetrazol (PTZ)-induced seizures. PTZ (30, 45 or 60 g/kg, i.p.) was administered to adult male Swiss mice, and Na(+),K(+)-ATPase activity and phosphorylation state were measured in the cerebral cortex 15 min after PTZ administration. Na(+),K(+)-ATPase activity significantly decreased after PTZ-induced seizures (60 mg/kg). Immunoreactivity of phosphorylated Ser943 at α subunit was increased after PTZ-induced seizures. A significant positive correlation between Na(+),K(+)-ATPase activity and latency to myoclonic jerks and generalized seizures was found. Conversely, a strong negative correlation between Ser943 phosphorylation and latency to generalized seizures was detected. Given the role of Na(+),K(+)-ATPase as a major regulator of brain excitability, Ser943 at Na(+),K(+)-ATPase α subunit may represent a potentially valuable new target for drug development for seizure disorders. PMID:23602551

  1. Fish oil supplementation associated with decreased cellular degeneration and increased cellular proliferation 6 weeks after middle cerebral artery occlusion in the rat.

    PubMed

    Pascoe, Michaela C; Howells, David W; Crewther, David P; Carey, Leeanne M; Crewther, Sheila G

    2015-01-01

    Anti-inflammatory long-chain omega-3 polyunsaturated fatty acids (n-3-LC-PUFAs) are both neuroprotective and have antidepressive effects. However the influence of dietary supplemented n-3-LC-PUFAs on inflammation-related cell death and proliferation after middle cerebral artery occlusion (MCAo)-induced stroke is unknown. We have previously demonstrated that anxiety-like and hyperactive locomotor behaviors are reduced in n-3-LC-PUFA-fed MCAo animals. Thus in the present study, male hooded Wistar rats were exposed to MCAo or sham surgeries and examined behaviorally 6 weeks later, prior to euthanasia and examination of lesion size, cell death and proliferation in the dentate gyrus, cornu ammonis region of the hippocampus of the ipsilesional hemispheres, and the thalamus of the ipsilesional and contralesional hemispheres. Markers of cell genesis and cell degeneration in the hippocampus or thalamus of the ipsilesional hemisphere did not differ between surgery and diet groups 6 weeks post MCAo. Dietary supplementation with n-3-LC-PUFA decreased cell degeneration and increased cell proliferation in the thalamic region of the contralesional hemisphere. MCAo-associated cell degeneration in the hippocampus and thalamus positively correlated with anxiety-like and hyperactive locomotor behaviors previously reported in these animals. These results suggest that anti-inflammatory n-3-LC-PUFA supplementation appears to have cellular protective effects after MCAo in the rat, which may affect behavioral outcomes. PMID:25609971

  2. Cerebral Blood Flow in Posterior Cortical Nodes of the Default Mode Network Decreases with Task Engagement but Remains Higher than in Most Brain Regions

    PubMed Central

    Pfefferbaum, Adolf; Chanraud, Sandra; Pitel, Anne-Lise; Müller-Oehring, Eva; Shankaranarayanan, Ajit; Alsop, David C.; Rohlfing, Torsten

    2011-01-01

    Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic “default mode network” and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion. PMID:20484322

  3. Fish oil supplementation associated with decreased cellular degeneration and increased cellular proliferation 6 weeks after middle cerebral artery occlusion in the rat

    PubMed Central

    Pascoe, Michaela C; Howells, David W; Crewther, David P; Carey, Leeanne M; Crewther, Sheila G

    2015-01-01

    Anti-inflammatory long-chain omega-3 polyunsaturated fatty acids (n-3-LC-PUFAs) are both neuroprotective and have antidepressive effects. However the influence of dietary supplemented n-3-LC-PUFAs on inflammation-related cell death and proliferation after middle cerebral artery occlusion (MCAo)-induced stroke is unknown. We have previously demonstrated that anxiety-like and hyperactive locomotor behaviors are reduced in n-3-LC-PUFA-fed MCAo animals. Thus in the present study, male hooded Wistar rats were exposed to MCAo or sham surgeries and examined behaviorally 6 weeks later, prior to euthanasia and examination of lesion size, cell death and proliferation in the dentate gyrus, cornu ammonis region of the hippocampus of the ipsilesional hemispheres, and the thalamus of the ipsilesional and contralesional hemispheres. Markers of cell genesis and cell degeneration in the hippocampus or thalamus of the ipsilesional hemisphere did not differ between surgery and diet groups 6 weeks post MCAo. Dietary supplementation with n-3-LC-PUFA decreased cell degeneration and increased cell proliferation in the thalamic region of the contralesional hemisphere. MCAo–associated cell degeneration in the hippocampus and thalamus positively correlated with anxiety-like and hyperactive locomotor behaviors previously reported in these animals. These results suggest that anti-inflammatory n-3-LC-PUFA supplementation appears to have cellular protective effects after MCAo in the rat, which may affect behavioral outcomes. PMID:25609971

  4. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    PubMed

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05). Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05). These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction. PMID:24315581

  5. Peripherally Applied Synthetic Tetrapeptides HAEE and RADD Slow Down the Development of Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice.

    PubMed

    Tsvetkov, Philipp O; Cheglakov, Ivan B; Ovsepyan, Armen A; Mediannikov, Oleg Y; Morozov, Alexander O; Telegin, Georgy B; Kozin, Sergey A

    2015-01-01

    Two tetrapeptides, HAEE and RADD, which are ionic-complementary to the primary zinc recognition site of amyloid-β (Aβ), have been reported to inhibit zinc-induced dimerization of the Aβ metal-binding domain and slow Aβ aggregation in vitro. In the present study, we investigate the impact of HAEE and RADD on the development of cerebral β-amyloidosis in a mouse model of Alzheimer's disease. We have found chronic intravenous administration of each peptide results in significant decrease of amyloid plaque burden in the treated mice. PMID:26402624

  6. Non-amyloid and amyloid prion protein deposits in prion-infected mice differ in blockage of interstitial brain fluid

    PubMed Central

    Rangel, Alejandra; Race, Brent; Striebel, James; Chesebro, Bruce

    2012-01-01

    Aims Prion diseases are characterized by brain deposits of misfolded aggregated protease-resistant prion protein (PrP), termed PrPres. In humans and animals, PrPres is found as either disorganized non-amyloid aggregates or organized amyloid fibrils. Both PrPres forms are found in extracellular spaces of the brain. Thus, both might block drainage of brain interstitial fluid (ISF). The present experiments studied whether ISF blockage occurred during amyloid and/or non-amyloid prion diseases. Methods Various-sized fluorescein-labeled ISF tracers were stereotactically inoculated into the striatum of adult mice. At times from 5 min to 77 hours, uninfected and scrapie-infected mice were compared. C57BL/10 mice expressing wild-type anchored PrP, which develop non-amyloid PrPres similar to humans with sporadic CJD, were compared with Tg44+/+ mice expressing anchorless PrP, which develop amyloid PrPres similar to certain human familial prion diseases. Results In C57BL/10 mice, extensive non-amyloid PrPres aggregate deposition was not associated with abnormal clearance kinetics of tracers. In contrast, scrapie-infected Tg44+/+ mice showed blockage of tracer clearance and co-localization of tracer with perivascular PrPres amyloid. Conclusions Since tracer localization and clearance was normal in infected C57BL/10 mice, ISF blockage was not an important pathogenic mechanism in this model. Therefore, ISF blockage is unlikely to be a problem in non-amyloid human prion diseases such as sporadic CJD. In contrast, partial ISF blockage appeared to be a possible pathogenic mechanism in Tg44+/+ mice. Thus this mechanism might also influence human amyloid prion diseases where expression of anchorless or mutated PrP results in perivascular amyloid PrPres deposition and cerebral amyloid angiopathy (CAA). PMID:22998478

  7. Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide*

    PubMed Central

    Aston-Mourney, Kathryn; Zraika, Sakeneh; Udayasankar, Jayalakshmi; Subramanian, Shoba L.; Green, Pattie S.; Kahn, Steven E.; Hull, Rebecca L.

    2013-01-01

    Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes. PMID:23229548

  8. Curcumin treatment recovery the decrease of protein phosphatase 2A subunit B induced by focal cerebral ischemia in Sprague-Dawley rats

    PubMed Central

    Shah, Fawad-Ali; Park, Dong-Ju; Gim, Sang-Ah

    2015-01-01

    Curcumin provides various biological effects through its anti-inflammatory and antioxidant properties. Moreover, curcumin exerts a neuroprotective effect against ischemic condition-induced brain damage. Protein phosphatase 2A (PP2A) is a ubiquitous serine and threonine phosphatase with various cell functions and broad substrate specificity. Especially PP2A subunit B plays an important role in nervous system. This study investigated whether curcumin regulates PP2A subunit B expression in focal cerebral ischemia. Cerebral ischemia was induced surgically by middle cerebral artery occlusion (MCAO). Adult male rats were injected with either vehicle or curcumin (50 mg/kg) 1 h after MCAO and cerebral cortex tissues were isolated 24 h after MCAO. A proteomics study, reverse transverse-PCR and Western blot analyses were performed to examine PP2A subunit B expression levels. We identified a reduction in PP2A subunit B expression in MCAO-operated animals using a proteomic approach. However, curcumin treatment prevented injury-induced reductions in PP2A subunit B levels. Reverse transverse-PCR and Western blot analyses confirmed that curcumin treatment attenuated the injury-induced reduction in PP2A subunit B levels. These findings can suggest that the possibility that curcumin maintains levels of PP2A subunit B in response to cerebral ischemia, which likely contributes to the neuroprotective function of curcumin in cerebral ischemic injury. PMID:26472966

  9. Diphenyl diselenide, a simple organoselenium compound, decreases methylmercury-induced cerebral, hepatic and renal oxidative stress and mercury deposition in adult mice.

    PubMed

    de Freitas, Andressa Sausen; Funck, Vinícius Rafael; Rotta, Mariana dos Santos; Bohrer, Denise; Mörschbächer, Vanessa; Puntel, Robson Luís; Nogueira, Cristina Wayne; Farina, Marcelo; Aschner, Michael; Rocha, João Batista Teixeira

    2009-04-01

    Oxidative stress has been pointed out as an important molecular mechanism in methylmercury (MeHg) intoxication. At low doses, diphenyl diselenide ((PhSe)2), a structurally simple organoselenium compound, has been shown to possess antioxidant and neuroprotective properties. Here we have examined the possible in vivo protective effect of diphenyl diselenide against the potential pro-oxidative effects of MeHg in mouse liver, kidney, cerebrum and cerebellum. The effects of MeHg exposure (2 mg/(kg day) of methylmercury chloride 10 ml/kg, p.o.), as well as the possible antagonist effect of diphenyl diselenide (1 and 0.4 mg/(kg day); s.c.) on body weight gain and on hepatic, cerebellar, cerebral and renal levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), ascorbic acid content, mercury concentrations and activities of antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) were evaluated after 35 days of treatment. MeHg caused an increase in TBARS and decreased NPSH levels in all tissues. MeHg also induced a decrease in hepatic ascorbic acid content and in renal GPx and CAT activities. Diphenyl diselenide (1 mg/kg) conferred protection against MeHg-induced hepatic and renal lipid peroxidation and at both doses prevented the reduction in hepatic NPSH levels. Diphenyl diselenide also conferred a partial protection against MeHg-induced oxidative stress (TBARS and NPSH) in liver and cerebellum. Of particular importance, diphenyl diselenide decreased the deposition of Hg in cerebrum, cerebellum, kidney and liver. The present results indicate that diphenyl diselenide can protect against some toxic effects of MeHg in mice. This protection may be related to its antioxidant properties and its ability to reduce Hg body burden. We posit that formation of a selenol intermediate, which possesses high nucleophilicity and high affinity for MeHg, accounts for the ability of diphenyl diselenide to ameliorate Me

  10. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders.

    PubMed

    Batarseh, Yazan S; Duong, Quoc-Viet; Mousa, Youssef M; Al Rihani, Sweilem B; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer's disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  11. Plasma β-amyloid in Alzheimer’s disease and vascular disease

    PubMed Central

    Janelidze, Shorena; Stomrud, Erik; Palmqvist, Sebastian; Zetterberg, Henrik; van Westen, Danielle; Jeromin, Andreas; Song, Linan; Hanlon, David; Tan Hehir, Cristina A.; Baker, David; Blennow, Kaj; Hansson, Oskar

    2016-01-01

    Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of Aβ42 and Aβ40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both Aβ42 and Aβ40, and negative correlations between plasma Aβ42 and neocortical amyloid deposition (measured with PET). Plasma levels of Aβ42 and Aβ40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of Aβ42 was just moderately decreased whereas Aβ40 levels were unchanged. Higher plasma (but not CSF) levels of Aβ were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma Aβ is overtly decreased during the dementia stage of AD indicating that prominent changes in Aβ metabolism occur later in the periphery compared to the brain. Further, increased levels of Aβ in plasma are associated with vascular disease. PMID:27241045

  12. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice

    PubMed Central

    Heilbronner, Götz; Eisele, Yvonne S; Langer, Franziska; Kaeser, Stephan A; Novotny, Renata; Nagarathinam, Amudha; Åslund, Andreas; Hammarström, Per; Nilsson, K Peter R; Jucker, Mathias

    2013-01-01

    The polymorphic β-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral β-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop β-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Aβ40/Aβ42 peptide ratio. To determine the nature of such β-amyloid morphotypes, β-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced β-amyloid deposition with the morphological, conformational, and Aβ40/Aβ42 ratio characteristics of β-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced β-amyloid deposits with the characteristics of β-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced β-amyloid deposits, although less prominent, and the induced deposits were similar to the β-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Aβ in APP transgenic mice can be maintained by seeded conversion. PMID:23999102

  13. Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies.

    PubMed

    Hallé, Maxime; Tribout-Jover, Pascale; Lanteigne, Anne-Marie; Boulais, Jonathan; St-Jean, Julien R; Jodoin, Rachel; Girouard, Marie-Pier; Constantin, Florin; Migneault, Annik; Renaud, Frédéric; Didierlaurent, Arnaud M; Mallett, Corey P; Burkhart, David; Pilorget, Anthony; Palmantier, Rémi; Larocque, Daniel

    2015-09-01

    Antibody-mediated capture of amyloid-beta (Aβ) in peripheral blood was identified as an attractive strategy to eliminate cerebral toxic amyloid in Alzheimer's disease (AD) patients and murine models. Alternatively, defective capacity of peripheral monocytes to engulf Aβ was reported in individuals with AD. In this report, we developed different approaches to investigate cellular uptake and phagocytosis of Aβ, and to examine how two immunological devices--an immunostimulatory Adjuvant System and different amyloid specific antibodies--may affect these biological events. Between one and thirteen months of age, APPswe X PS1.M146V (TASTPM) AD model mice had decreasing concentrations of Aβ in their plasma. In contrast, the proportion of blood monocytes containing Aβ tended to increase with age. Importantly, the TLR-agonist containing Adjuvant System AS01B primed monocytes to promote de novo Aβ uptake capacity, particularly in the presence of anti-Aβ antibodies. Biochemical experiments demonstrated that cells achieved Aβ uptake and internalization followed by Aβ degradation via mechanisms that required effective actin polymerization and proteolytic enzymes such as insulin-degrading enzyme. We further demonstrated that both Aβ-specific monoclonal antibodies and plasma from Aβ-immunized mice enhanced the phagocytosis of 1 μm Aβ-coated particles. Together, our data highlight a new biomarker testing to follow amyloid clearance within the blood and a mechanism of Aβ uptake by peripheral monocytes in the context of active or passive immunization, and emphasize on novel approaches to investigate this phenomenon. PMID:26002154

  14. Biofilm Inhibitors that Target Amyloid Proteins

    PubMed Central

    Romero, Diego; Sanabria-Valentín, Edgardo; Vlamakis, Hera; Kolter, Roberto

    2012-01-01

    Summary Bacteria establish stable communities, known as biofilms, that are resistant to antimicrobials. Biofilm robustness is due to the presence of an extracellular matrix, which for several species - among them Bacillus subtilis - includes amyloid-like protein fibers. In this work, we show that B. subtilis biofilms can be a simple and reliable tool for screening of molecules with anti-amyloid activity. We identified two molecules, AA-861 and parthenolide, which efficiently inhibited biofilms by preventing the formation of amyloid-like fibers. We found that parthenolide also disrupted pre-established biofilms. These molecules also impeded the formation of biofilms of other bacterial species that secrete amyloid proteins, such as Bacillus cereus and Escherichia coli. Furthermore, the identified molecules decreased the conversion of the yeast protein New1 to the prion state in a heterologous host, indicating the broad range of activity of the molecules. PMID:23352144

  15. Cerebral Palsy

    MedlinePlus

    ... How Can I Help a Friend Who Cuts? Cerebral Palsy KidsHealth > For Teens > Cerebral Palsy Print A A ... do just what everyone else does. What Is Cerebral Palsy? Cerebral palsy (CP) is a disorder of the ...

  16. Amyloid goes global

    PubMed Central

    Bezprozvanny, Ilya

    2016-01-01

    The brains of Alzheimer’s disease (AD) patients contain abundant amyloid plaques composed of Aβ peptides. It is generally assumed that amyloid plaques and soluble Aβ oligomers induce neuronal pathology in AD. The mechanism of amyloid-mediated pathological effects is not clearly understood. Recent in vivo calcium (Ca2+) imaging studies with AD mouse models provide novel insights into changes in brain function resulting from accumulation of amyloid plaques. The unexpected lesson from these studies is that amyloid plaques result in both localized and global changes in brain function. The amyloid-induced effects include “short-range” changes in neuronal Ca2+ levels, “medium-range” changes in neuronal activity and ‘long-range” changes in astrocytic Ca2+ signaling and induction of intracellular Ca2+ waves spreading via astrocytic network. These results have potential implications for understanding synaptic and neuronal network dysfunction in AD brains. PMID:19318622

  17. Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats

    PubMed Central

    Li, Lingyu; Xiao, Lina; Hou, Yanghao; He, Qi; Zhu, Jin; Li, Yixin; Wu, Jingxian; Zhao, Jing; Yu, Shanshan; Zhao, Yong

    2016-01-01

    Sestrin2 (Sesn2) exerts neuroprotective properties in some neurodegenerative diseases. However, the role of Sesn2 in stroke is unclear. The AMP-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator-1α (AMPK/PGC-1α) pathway plays an important role in regulating mitochondrial biogenesis, which helps prevent cerebral ischemia/reperfusion (I/R) injury. Here, we aimed to determine whether Sesn2 alleviated I/R damage by regulating mitochondrial biogenesis through the AMPK/PGC-1α signaling pathway. To be able to test this, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h with Sesn2 silencing. At 24 h after reperfusion, we found that neurological deficits were exacerbated, infarct volume was enlarged, and oxidative stress and neuronal damage were greater in the Sesn2 siRNA group than in the MCAO group. To explore protective mechanisms, an AMPK activator was used. Expression levels of Sesn2, p-AMPK, PGC-1α, NRF-1, TFAM, SOD2, and UCP2 were significantly increased following cerebral I/R. However, upregulation of these proteins was prevented by Sesn2 small interfering RNA (siRNA). In contrast, activation of AMPK with 5′-aminoimidazole-4-carboxamide riboside weakened the effects of Sesn2 siRNA. These results suggest that Sesn2 silencing may suppress mitochondrial biogenesis, reduce mitochondrial biological activity, and finally aggravate cerebral I/R injury through inhibiting the AMPK/PGC-1α pathway. PMID:27453548

  18. Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model.

    PubMed

    Dong, Wen; Qi, Zhifeng; Liang, Jia; Shi, Wenjuan; Zhao, Yongmei; Luo, Yumin; Ji, Xunming; Liu, Ke Jian

    2015-10-01

    Cerebral ischemia interrupts oxygen supply to the affected tissues. Our previous studies have reported that normobaric hyperoxia (NBO) can maintain interstitial partial pressure of oxygen (pO2) in the penumbra of ischemic stroke rats at the physiological level, thus affording significant neuroprotection. However, the mechanisms that are responsible for the penumbra rescue by NBO treatment are not fully understood. Recent studies have shown that zinc, an important mediator of intracellular and intercellular neuronal signaling, accumulates in neurons and leads to ischemic neuronal injury. In this study, we investigate whether NBO could regulate zinc accumulation in the penumbra and prevent mitochondrial damage in penumbral tissue using a transient cerebral ischemic rat model. Our results showed that NBO significantly reduced zinc-staining positive cells and zinc-staining intensity in penumbral tissues, but not in the ischemic core. Moreover, ischemia-induced zinc accumulation in mitochondria, isolated from penumbral tissues, was greatly attenuated by NBO or a zinc-specific chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). NBO or TPEN administration stabilized the mitochondrial membrane potential in the penumbra after cerebral ischemia. Finally, ischemia-induced cytochrome c release from mitochondria in penumbral tissues was significantly reduced by NBO or TPEN treatment. These findings demonstrate a novel mechanism for NBO's neuroprotection, especially to penumbral tissues, providing further evidence for the potential clinical benefit of NBO for acute ischemic stroke. PMID:25891441

  19. [Amyloid angiopathy as a clinico-pathological entity to consider in the differential diagnosis of any hemorrhagic cerebrovascular accident].

    PubMed

    Miras Parra, F J; Valverde Romera, M; Gómez Jiménez, F J; de la Higuera Torres-Puchol, J; Cantero Hinojosa, J; Sánchez Parera, R

    1996-06-01

    Intracerebral hemorrhages represent about 10% of the whole of vascular cerebral accidents. According to different authors, the incidence of cerebral amyloid angiopathy varies between 5-10% and up to 20-30% of all primary non-traumatic intracerebral hemorrhages. This incidence was analyzed in our environment. A retrospective study was carried out on 403 patients, 203 of them were analyzed between 1990-91 and the other 200 between 1992-3. Age, arterial tension, relapses and localization were taken as criteria for a diagnosis. For the statistical analysis, Student's T-test was used for quantitative variables, while square Chi with Yates' correction was used for qualitative variables. Ischemic cerebral accidents (90.5% of the total) are more frequent than hemorrhagic cerebral accidents, which represent 5.7%. 3.7% were not registered. Therefore, it was suspected cerebral amyloid angiopathy in 1.4% of all vascular cerebral accidents. This represents 26.1% of the total of hemorrhagic patients. Different variables from groups of hemorrhagic vascular cerebral accidents were compared to those caused by amyloid cerebral angiopathy and significant statistics were found with respect to localization in the cerebral hemispheres (p < 0.01). Neither age, nor arterial tension or relapses were significant. Amyloid cerebral angiopathy as a cause of hemorrhagic cerebrovascular accident is and entity to be considered in the diagnosis of these patients. By using clinical criteria and others of localization through complementary explorations, a diagnosis for guessing such a process can be determined. PMID:8962954

  20. Plasticity of amyloid fibrils†

    PubMed Central

    Wetzel, Ronald; Shivaprasad, Shankaramma; Williams, Angela D.

    2008-01-01

    In experiments designed to characterize the basis of amyloid fibril stability through mutational analysis of the Aβ(1-40) molecule, fibrils exhibit consistent, significant structural malleability. In these results, and in other properties, amyloid fibrils appear to more resemble plastic materials generated from synthetic polymers than they do globular proteins. Thus, like synthetic polymers and plastics, amyloid fibrils exhibit both polymorphism, the ability of one polypeptide to form aggregates of different morphologies, and isomorphism, the ability of different polypeptides to grow into a fibrillar amyloid morphology. This view links amyloid with the prehistorical and 20th Century use of proteins as starting materials to make films, fibers, and plastics, and with the classic protein fiber stretching experiments of the Astbury group. Viewing amyloid from the point of view of the polymer chemist may shed new light on issues such as the role of protofibrils in the mechanism of amyloid formation, the biological potency of fibrils, and the prospects for discovering inhibitors of amyloid fibril formation. PMID:17198370

  1. Contrasting effects of nanoparticle-protein attraction on amyloid aggregation

    PubMed Central

    Radic, Slaven; Davis, Thomas P; Ke, Pu Chun; Ding, Feng

    2015-01-01

    Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases. PMID:26989481

  2. Cerebral level of vGlut1 is increased and level of glycine is decreased in TgSwDI mice.

    PubMed

    Timmer, Nienke M; Metaxas, Athanasios; van der Stelt, Inge; Kluijtmans, Leo A J; van Berckel, Bart N; Verbeek, Marcel M

    2014-01-01

    Amyloid-β (Aβ) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Aβ on multiple components of the glutamatergic system, and therefore we assessed the expression of several glutamate-related proteins and amino acids in the TgSwDI mouse model for Aβ pathology. We determined that in TgSwDI mice, levels of several amino acids are altered, in particular that of glycine. Protein changes were only found in 9-month-old TgSwDI mice with extensive Aβ deposits, with the most prominent change an increased expression of vesicular glutamate transporter 1 (vGlut1). Autoradiography experiments demonstrated that, while the number of activated N-methyl-D-aspartic acid (NMDA) receptors was unchanged in TgSwDI mice, binding of the NMDA receptor radioligand [3H]MDL-105,519 to the glycine-binding site of these receptors was increased. Although there are some discrepancies between our results and those found in AD patients, our results suggest that several components of the glutamatergic system might serve as meaningful markers to monitor the progression of AD. PMID:24145381

  3. Magnetic fluid - a novel approach to treat amyloid-related diseases

    NASA Astrophysics Data System (ADS)

    Antosova, Andrea; Siposova, Katarina; Koneracka, Martina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fedunova, Diana; Bagelova, Jaroslava; Kopcansky, Peter; Gazova, Zuzana

    Protein amyloid aggregates are associated with several human pathologies termed amyloid-related diseases. We have investigated effect of two magnetic fluids (MFs) - electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate with adsorbed BSA (MF2) on amyloid aggregation of two proteins - human insulin and hen egg lysozyme. We have found that both MF1 and MF2 are able to interact with amyloid fibrils in vitro resulting into decreasing of amyloid aggregates. The extent of fibril disruption depends on MF concentration with extensive reduction of amyloid aggregates, 90% for lysozyme and 70% for insulin (ratio protein: MF=1:5). The obtained results suggest that magnetite component of MF play significant role in the process of amyloid fibril depolymerisation. Our findings indicate that MF1 and MF2 have potential to be used for treatment of amyloid diseases.

  4. Evidence for the experimental transmission of cerebral beta-amyloidosis to primates.

    PubMed Central

    Baker, H. F.; Ridley, R. M.; Duchen, L. W.; Crow, T. J.; Bruton, C. J.

    1993-01-01

    The brains of three marmosets (Callithrix jacchus) injected intracerebrally 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease were found to contain moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy but no neurofibrillary tangles. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of three age-matched control marmosets from the same colony did not show these neuropathological features. The brain of one of two marmosets injected with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and cerebral amyloid angiopathy also showed beta-amyloid plaques and angiopathy but no spongiform encephalopathy. An occasional plaque was found in the brains of two of four marmosets injected with brain tissue from three elderly patients with age-related pathology, two of whom had an additional diagnosis of possible prion disease. Neither plaques nor cerebral amyloid angiopathy were found in six other marmosets who were older than the injected animals, in 12 further marmosets who were slightly younger but who had been injected several years previously with brain tissue which did not contain beta-amyloid, or in 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that cerebral beta-amyloidosis may be induced by the introduction of exogenous amyloid beta-protein. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8217779

  5. Cerebral microbleeds as a biomarker in Alzheimer's disease? A review in the field.

    PubMed

    Shams, Sara; Wahlund, Lars-Olof

    2016-01-01

    Cerebral microbleeds (CMBs) are a marker of small vessel disease, increasingly recognized as being of importance in the Alzheimer's disease (AD) process. CMBs influence in AD, and its longitudinal impact on disease progression is however still unknown. CMBs show several associations with AD across studies, are associated with decreased cerebrospinal fluid amyloid levels and are related with the ApoE ϵ4 allele, as well as other imaging manifestations typical for small vessel disease. CMBs, in addition to other markers of small vessel disease, are important to discover further in order to discern possible AD phenotypes. PMID:26641942

  6. Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits.

    PubMed

    Agyare, Edward K; Jaruszewski, Kristen M; Curran, Geoffry L; Rosenberg, Jens T; Grant, Samuel C; Lowe, Val J; Ramakrishnan, Subramanian; Paravastu, Anant K; Poduslo, Joseph F; Kandimalla, Karunya K

    2014-07-10

    Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation leading to recurrent hemorrhagic strokes. The objective of the study was to develop theranostic nanovehicles (TNVs) capable of a) targeting cerebrovascular amyloid; b) providing magnetic resonance imaging (MRI) contrast for the early detection of CAA; and c) treating cerebrovascular inflammation resulting from CAA. The TNVs comprised of a polymeric nanocore made from Magnevist (MRI contrast agent) conjugated chitosan. The nanocore was also loaded with cyclophosphamide (CYC), an immunosuppressant shown to reduce the cerebrovascular inflammation in CAA. Putrescine modified F(ab')2 fragment of anti-amyloid antibody, IgG4.1 (pF(ab')24.1) was conjugated to the surface of the nanocore to target cerebrovascular amyloid. The average size of the control chitosan nanoparticles (conjugated with albumin and are devoid of Magnevist, CYC, and pF(ab')24.1) was 164±1.2 nm and that of the TNVs was 239±4.1 nm. The zeta potential values of the CCNs and TNVs were 21.6±1.7 mV and 11.9±0.5 mV, respectively. The leakage of Magnevist from the TNVs was a modest 0.2% over 4 days, and the CYC release from the TNVs followed Higuchi's model that describes sustained drug release from polymeric matrices. The studies conducted in polarized human microvascular endothelial cell monolayers (hCMEC/D3) in vitro as well as in mice in vivo have demonstrated the ability of TNVs to target cerebrovascular amyloid. In addition, the TNVs provided contrast for imaging cerebrovascular amyloid using MRI and single photon emission computed tomography. Moreover, the TNVs were shown to reduce pro-inflammatory cytokine production by the Aβ challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone. PMID:24735640

  7. Cerebral Hypoxia

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  8. Cerebral blood flow velocity in two patients with neonatal cerebral infarction.

    PubMed

    Nishimaki, S; Seki, K; Yokota, S

    2001-04-01

    Cerebral blood flow velocity was measured in the middle cerebral artery of two patients who exhibited unilateral neonatal cerebral infarction during the neonatal period. Doppler studies demonstrated increases in cerebral blood flow velocity but decreases in the resistance index on the affected side of the middle cerebral artery in the neonate who developed hemiplegia with cystic encephalomalacia, although the neonate with normal neurologic outcome exhibited symmetric cerebral blood flow velocity and resistance index. The asymmetry in cerebral blood flow velocity measurements of both middle cerebral arteries may be useful to evaluate the severity of brain damage and predict the neurodevelopmental prognosis of unilateral neonatal cerebral infarction. PMID:11377112

  9. Cerebral β-Amyloidosis in Mice Investigated by Ultramicroscopy

    PubMed Central

    Jährling, Nina; Becker, Klaus; Wegenast-Braun, Bettina M.; Grathwohl, Stefan A.; Jucker, Mathias; Dodt, Hans-Ulrich

    2015-01-01

    Alzheimer´s disease (AD) is the most common neurodegenerative disorder. AD neuropathology is characterized by intracellular neurofibrillary tangles and extracellular β-amyloid deposits in the brain. To elucidate the complexity of AD pathogenesis a variety of transgenic mouse models have been generated. An ideal imaging system for monitoring β-amyloid plaque deposition in the brain of these animals should allow 3D-reconstructions of β-amyloid plaques via a single scan of an uncropped brain. Ultramicroscopy makes this possible by replacing mechanical slicing in standard histology by optical sectioning. It allows a time efficient analysis of the amyloid plaque distribution in the entire mouse brain with 3D cellular resolution. We herein labeled β-amyloid deposits in a transgenic mouse model of cerebral β-amyloidosis (APPPS1 transgenic mice) with two intraperitoneal injections of the amyloid-binding fluorescent dye methoxy-X04. Upon postmortem analysis the total number of β-amyloid plaques, the β-amyloid load (volume percent) and the amyloid plaque size distributions were measured in the frontal cortex of two age groups (2.5 versus 7-8.5 month old mice). Applying ultramicroscopy we found in a proof-of-principle study that the number of β-amyloid plaques increases with age. In our experiments we further observed an increase of large plaques in the older age group of mice. We demonstrate that ultramicroscopy is a fast, and accurate analysis technique for studying β-amyloid lesions in transgenic mice allowing the 3D staging of β-amyloid plaque development. This in turn is the basis to study neural network degeneration upon cerebral β-amyloidosis and to assess Aβ -targeting therapeutics. PMID:26017149

  10. Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis

    PubMed Central

    Liao, Fan; Hori, Yukiko; Hudry, Eloise; Bauer, Adam Q.; Jiang, Hong; Mahan, Thomas E.; Lefton, Katheryn B.; Zhang, Tony J.; Dearborn, Joshua T.; Kim, Jungsu; Culver, Joseph P.; Betensky, Rebecca; Wozniak, David F.; Hyman, Bradley T.

    2014-01-01

    Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology. PMID:24849360

  11. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    PubMed Central

    Cai, Zhiyou; Yan, Yong; Wang, Yonglong

    2013-01-01

    Background Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions

  12. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    PubMed Central

    Batarseh, Yazan S.; Duong, Quoc-Viet; Mousa, Youssef M.; Al Rihani, Sweilem B.; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  13. Precursor protein of Alzheimer's disease A4 amyloid is encoded by 16 exons

    SciTech Connect

    Lemaire, H.G.; Kang, J.; Mueller-Hill, B. ); Salbaum, J.M.; Multhaup, G.; Beyreuther, K. ); Bayney, R.M.; Unterbeck, A. )

    1989-01-25

    Alzheimer's disease (AD) is characterized by the cerebral deposition of fibrillar aggregates of the amyloid A4 protein. Complementary DNA's coding for the precursor of the amyloid A4 protein have been described. In order to identify the structure of the precursor gene relevant clones from several human genomic libraries were isolated. Sequence analysis of the various clones revealed 16 exons to encode the 695 residue precursor protein (PreA4{sub 695}) of Alzheimer's disease amyloid A4 protein. The DNA sequence coding for the amyloid A4 protein is interrupted by an intron. This finding supports the idea that amyloid A4 protein arises by incomplete proteolysis of a larger precursor, and not by aberrant splicing.

  14. In situ hybridization of nucleus basalis neurons shows increased. beta. -amyloid mRNA in Alzheimer disease

    SciTech Connect

    Cohen, M.L.; Golde, T.E.; Usiak, M.F.; Younkin, L.H.; Younkin, S.G.

    1988-02-01

    To determine which cells within the brain produce ..beta..-amyloid mRNA and to assess expression of the ..beta..-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that ..beta..-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more ..beta..-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the ..beta..-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease.

  15. Hydrogen Sulfide Inhibits Amyloid Formation

    PubMed Central

    2015-01-01

    Amyloid fibrils are large aggregates of misfolded proteins, which are often associated with various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and vascular dementia. The amount of hydrogen sulfide (H2S) is known to be significantly reduced in the brain tissue of people diagnosed with Alzheimer’s disease relative to that of healthy individuals. These findings prompted us to investigate the effects of H2S on the formation of amyloids in vitro using a model fibrillogenic protein hen egg white lysozyme (HEWL). HEWL forms typical β-sheet rich fibrils during the course of 70 min at low pH and high temperatures. The addition of H2S completely inhibits the formation of β-sheet and amyloid fibrils, as revealed by deep UV resonance Raman (DUVRR) spectroscopy and ThT fluorescence. Nonresonance Raman spectroscopy shows that disulfide bonds undergo significant rearrangements in the presence of H2S. Raman bands corresponding to disulfide (RSSR) vibrational modes in the 550–500 cm–1 spectral range decrease in intensity and are accompanied by the appearance of a new 490 cm–1 band assigned to the trisulfide group (RSSSR) based on the comparison with model compounds. The formation of RSSSR was proven further using a reaction with TCEP reduction agent and LC-MS analysis of the products. Intrinsic tryptophan fluorescence study shows a strong denaturation of HEWL containing trisulfide bonds. The presented evidence indicates that H2S causes the formation of trisulfide bridges, which destabilizes HEWL structure, preventing protein fibrillation. As a result, small spherical aggregates of unordered protein form, which exhibit no cytotoxicity by contrast with HEWL fibrils. PMID:25545790

  16. Amyloid Beta Mediates Memory Formation

    ERIC Educational Resources Information Center

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  17. Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid β protein antibody-coated nanoparticles.

    PubMed

    Poduslo, Joseph F; Hultman, Kristi L; Curran, Geoffry L; Preboske, Gregory M; Chamberlain, Ryan; Marjańska, Małgorzata; Garwood, Michael; Jack, Clifford R; Wengenack, Thomas M

    2011-08-01

    The relevance of cerebral amyloid angiopathy (CAA) to the pathogenesis of Alzheimer disease (AD) and dementia in general emphasizes the importance of developing novel targeting approaches for detecting and treating cerebrovascular amyloid (CVA) deposits. We developed a nanoparticle-based technology that uses a monoclonal antibody against fibrillar human amyloid-β42 that is surface coated onto a functionalized phospholipid monolayer. We demonstrate that this conjugated nanoparticle binds to CVA deposits in arterioles of AD transgenic mice (Tg2576) after infusion into the external carotid artery using 3 different approaches. The first 2 approaches use a blood vessel enrichment of homogenized brain and a leptomeningeal vessel preparation from thin tangential brain slices from the surface of the cerebral cortex. Targeting of CVA by the antibody-coated nanoparticle was visualized using fluorescent lissamine rhodamine-labeled phospholipids in the nanoparticles, which were compared with fluorescent staining of the endothelial cells and amyloid deposits using confocal laser scanning microscopy. The third approach used high-field strength magnetic resonance imaging of antibody-coated iron oxide nanoparticles after infusion into the external carotid artery. Dark foci of contrast enhancement in cortical arterioles were observed in T2*-weighted images of ex vivo AD mouse brains that correlated histologically with CVA deposits. The targeting ability of these nanoparticles to CVA provides opportunities for the prevention and treatment of CAA. PMID:21760540

  18. Adenoviral expression of murine serum amyloid A proteins to study amyloid fibrillogenesis.

    PubMed

    Kindy, M S; King, A R; Yu, J; Gerardot, C; Whitley, J; de Beer, F C

    1998-06-15

    Serum amyloid A (SAA) proteins are one of the most inducible acute-phase reactants and are precursors of secondary amyloidosis. In the mouse, SAA1 and SAA2 are induced in approximately equal quantities in response to amyloid induction models. These two isotypes differ in only 9 of 103 amino acid residues; however, only SAA2 is selectively deposited into amyloid fibrils. SAA expression in the CE/J mouse species is an exception in that gene duplication did not occur and the CE/J variant is a hybrid molecule sharing features of SAA1 and SAA2. However, even though it is more closely related to SAA2 it is not deposited as amyloid fibrils. We have developed an adenoviral vector system to overexpress SAA proteins in cell culture to determine the ability of these proteins to form amyloid fibrils, and to study the structural features in relation to amyloid formation. Both the SAA2 and CE/J SAA proteins were synthesized in large quantities and purified to homogeneity. Electron microscopic analysis of the SAA proteins revealed that the SAA2 protein was capable of forming amyloid fibrils, whereas the CE/J SAA was incapable. Radiolabelled SAAs were associated with normal or acute-phase high-density lipoproteins (HDLs); we examined them for their clearance from the circulation. In normal mice, SAA2 had a half-life of 70 min and CE/J SAA had a half-life of 120 min; however, in amyloid mice 50% of the SAA2 cleared in 55 min, compared with 135 min for the CE/J protein. When the SAA proteins were associated with acute-phase HDLs, SAA2 clearance was decreased to 60 min in normal mice compared with 30 min in amyloidogenic mice. Both normal and acute-phase HDLs were capable of depositing SAA2 into preformed amyloid fibrils, whereas the CE/J protein did not become associated with amyloid fibrils. This established approach opens the doors for large-scale SAA production and for the examination of specific amino acids involved in the fibrillogenic capability of the SAA2 molecule in vitro

  19. Amyloid Fibril Solubility.

    PubMed

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general. PMID:26496385

  20. Will PET amyloid imaging lead to overdiagnosis of Alzheimer dementia?

    PubMed

    Dubroff, Jacob G; Nasrallah, Ilya M

    2015-08-01

    Alzheimer disease (AD), a progressive neurodegenerative disease that causes dementia, affects millions of elderly Americans and represents a growing problem with the aging of the population. There has been an increasing effort for improved and earlier diagnosis for AD. Several newly developed radiolabeled compounds targeting β-amyloid plaques, one of the major pathologic biomarkers of AD, have recently become available for clinical use. These radiopharmaceuticals allow for in vivo noninvasive visualization of abnormal β-amyloid deposits in the brain using positron emission tomography (PET). Amyloid PET imaging has demonstrated high sensitivity for pathologic cerebral amyloid deposition in multiple studies. Principal drawbacks to this new diagnostic test are declining specificity in older age groups and uncertain clinical role given lack of disease-modifying therapy for AD. Although there is strong evidence for the utility of amyloid PET in certain situations, detailed in a set of guidelines for appropriate use from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the question of overdiagnosis, the diagnosis of a disease that would result in neither symptoms nor deaths, using this new medical tool needs to be carefully considered in light of efforts to secure reimbursement for the new technology that is already widely available for use as a clinical tool. PMID:26100192

  1. Juvenile traumatic brain injury induces long-term perivascular matrix changes alongside amyloid-beta accumulation

    PubMed Central

    Jullienne, Amandine; Roberts, Jill M; Pop, Viorela; Paul Murphy, M; Head, Elizabeth; Bix, Gregory J; Badaut, Jérôme

    2014-01-01

    In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Aβ) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Aβ clearance. Rodent-Aβ staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood–brain barrier alongside vascular dysfunction and altered Aβ trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions. PMID:25052558

  2. Cerebral Palsy

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Cerebral Palsy KidsHealth > For Kids > Cerebral Palsy Print A A ... the things that kids do every day. What's CP? Some kids with CP use wheelchairs and others ...

  3. Cerebral Palsy

    MedlinePlus

    ... Loss > Birth defects & other health conditions > Cerebral palsy Cerebral palsy E-mail to a friend Please fill in ... movement problems a child has. What is spastic CP? Spastic means tight or stiff muscles, or muscles ...

  4. Cerebral Palsy

    MedlinePlus

    Cerebral palsy is a group of disorders that affect a person's ability to move and to maintain balance ... do not get worse over time. People with cerebral palsy may have difficulty walking. They may also have ...

  5. Cerebral palsy

    MedlinePlus

    Cerebral palsy is a group of disorders that can involve brain and nervous system functions, such as movement, ... and thinking. There are several different types of cerebral palsy, including spastic, dyskinetic, ataxic, hypotonic, and mixed.

  6. Cerebral malaria.

    PubMed

    Postels, Douglas G; Birbeck, Gretchen L

    2013-01-01

    Malaria, the most significant parasitic disease of man, kills approximately one million people per year. Half of these deaths occur in those with cerebral malaria (CM). The World Health Organization (WHO) defines CM as an otherwise unexplained coma in a patient with malarial parasitemia. Worldwide, CM occurs primarily in African children and Asian adults, with the vast majority (greater than 90%) of cases occurring in children 5 years old or younger in sub-Saharan Africa. The pathophysiology of the disease is complex and involves infected erythrocyte sequestration, cerebral inflammation, and breakdown of the blood-brain barrier. A recently characterized malarial retinopathy is visual evidence of Plasmodium falciparum's pathophysiological processes occurring in the affected patient. Treatment consists of supportive care and antimalarial administration. Thus far, adjuvant therapies have not been shown to improve mortality rates or neurological outcomes in children with CM. For those who survive CM, residual neurological abnormalities are common. Epilepsy, cognitive impairment, behavioral disorders, and gross neurological deficits which include motor, sensory, and language impairments are frequent sequelae. Primary prevention strategies, including bed nets, vaccine development, and chemoprophylaxis, are in varied states of development and implementation. Continuing efforts to find successful primary prevention options and strategies to decrease neurological sequelae are needed. PMID:23829902

  7. Cerebral Small Vessel Disease: Targeting Oxidative Stress as a Novel Therapeutic Strategy?

    PubMed Central

    De Silva, T. Michael; Miller, Alyson A.

    2016-01-01

    Cerebral small vessel disease (SVD) is a major contributor to stroke, and a leading cause of cognitive impairment and dementia. Despite the devastating effects of cerebral SVD, the pathogenesis of cerebral SVD is still not completely understood. Moreover, there are no specific pharmacological strategies for its prevention or treatment. Cerebral SVD is characterized by marked functional and structural abnormalities of the cerebral microcirculation. The clinical manifestations of these pathological changes include lacunar infarcts, white matter hyperintensities, and cerebral microbleeds. The main purpose of this review is to discuss evidence implicating oxidative stress in the arteriopathy of both non-amyloid and amyloid (cerebral amyloid angiopathy) forms of cerebral SVD and its most important risk factors (hypertension and aging), as well as its contribution to cerebral SVD-related brain injury and cognitive impairment. We also highlight current evidence of the involvement of the NADPH oxidases in the development of oxidative stress, enzymes that are a major source of reactive oxygen species in the cerebral vasculature. Lastly, we discuss potential pharmacological strategies for oxidative stress in cerebral SVD, including some of the historical and emerging NADPH oxidase inhibitors. PMID:27014073

  8. Cerebral Palsy

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Cerebral Palsy Information Page Clinical Trials Trial of Erythropoietin Neuroprotection ... en Español Additional resources from MedlinePlus What is Cerebral Palsy? The term cerebral palsy refers to a group ...

  9. Cerebral Aneurysms

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Aneurysms Information Page Synonym(s): Aneurysm, Brain Aneurysm Condensed from ... Español Additional resources from MedlinePlus What is Cerebral Aneurysms? A cerebral aneurysm is a weak or thin ...

  10. A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.

    PubMed

    Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

    2016-05-01

    Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. PMID:26956423

  11. Current and future treatment of amyloid diseases.

    PubMed

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  12. Nucleation of amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Kashchiev, Dimo; Auer, Stefan

    2010-06-01

    We consider nucleation of amyloid fibrils in the case when the process occurs by the mechanism of direct polymerization of practically fully extended protein segments, i.e., β-strands, into β-sheets. Applying the classical nucleation theory, we derive a general expression for the work to form a nanosized amyloid fibril (protofilament) constituted of successively layered β-sheets. Analysis of this expression reveals that with increasing its size, the fibril transforms from one-dimensional to two-dimensional aggregate in order to preserve the equilibrium shape corresponding to minimal formation work. We determine the size of the fibril nucleus, the fibril nucleation work, and the fibril nucleation rate as explicit functions of the concentration and temperature of the protein solution. The results obtained are applicable to homogeneous nucleation, which occurs when the solution is sufficiently pure and/or strongly supersaturated.

  13. Intravenous Delivery of Targeted Liposomes to Amyloid-β Pathology in APP/PSEN1 Transgenic Mice

    PubMed Central

    Tanifum, Eric A.; Dasgupta, Indrani; Srivastava, Mayank; Bhavane, Rohan C.; Sun, Li; Berridge, John; Pourgarzham, Hoda; Kamath, Rashmi; Espinosa, Gabriela; Cook, Stephen C.; Eriksen, Jason L.; Annapragada, Ananth

    2012-01-01

    Extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles constitute the major neuropathological hallmarks of Alzheimer’s disease (AD). It is now apparent that parenchymal Aβ plaque deposition precedes behavioral signs of disease by several years. The development of agents that can target these plaques may be useful as diagnostic or therapeutic tools. In this study, we synthesized an Aβ-targeted lipid conjugate, incorporated it in stealth liposomal nanoparticles and tested their ability to bind amyloid plaque deposits in an AD mouse model. The results show that the particles maintain binding profiles to synthetic Aβ aggregates comparable to the free ligand, and selectively bind Aβ plaque deposits in brain tissue sections of an AD mouse model (APP/PSEN1 transgenic mice) with high efficiency. When administered intravenously, these long circulating nanoparticles appear to cross the blood-brain barrier and bind to Aβ plaque deposits, labeling parenchymal amyloid deposits and vascular amyloid characteristic of cerebral amyloid angiopathy. PMID:23119043

  14. Are amyloid fibrils molecular spandrels?

    PubMed

    Hane, Francis

    2013-11-15

    Amyloid-β, the protein implicated in Alzheimer's disease, along with a number of other proteins, has been shown to form amyloid fibrils. Fibril forming proteins share no common primary structure and have little known function. Furthermore, all proteins have the ability to form amyloid fibrils under certain conditions as the fibrillar structure lies at the global free energy minimum of proteins. This raises the question of the mechanism of the evolution of the amyloid fibril structure. Experimental evidence supports the hypothesis that the fibril structure is a by-product of the forces of protein folding and lies outside the bounds of evolutionary pressures. PMID:24140343

  15. Amyloids: from Pathogenesis to Function.

    PubMed

    Nizhnikov, A A; Antonets, K S; Inge-Vechtomov, S G

    2015-09-01

    The term "amyloids" refers to fibrillar protein aggregates with cross-β structure. They have been a subject of intense scrutiny since the middle of the previous century. First, this interest is due to association of amyloids with dozens of incurable human diseases called amyloidoses, which affect hundreds of millions of people. However, during the last decade the paradigm of amyloids as pathogens has changed due to an increase in understanding of their role as a specific variant of quaternary protein structure essential for the living cell. Thus, functional amyloids are found in all domains of the living world, and they fulfill a variety of roles ranging from biofilm formation in bacteria to long-term memory regulation in higher eukaryotes. Prions, which are proteins capable of existing under the same conditions in two or more conformations at least one of which having infective properties, also typically have amyloid features. There are weighty reasons to believe that the currently known amyloids are only a minority of their real number. This review provides a retrospective analysis of stages in the development of amyloid biology that during the last decade resulted, on one hand, in reinterpretation of the biological role of amyloids, and on the other hand, in the development of systems biology of amyloids, or amyloidomics. PMID:26555466

  16. Antimicrobial Properties of Amyloid Peptides

    PubMed Central

    Kagan, Bruce L.; Jang, Hyunbum; Capone, Ricardo; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Nussinov, Ruth

    2011-01-01

    More than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand-turn-β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that increased amounts of amyloids are not only toxic to its host target cells but also possess antimicrobial activity. Furthermore, at least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids. In this paper, we will review the reported antimicrobial properties of amyloids and the implications of these discoveries for our understanding of amyloid structure and function. PMID:22081976

  17. Oligomer Formation of Toxic and Functional Amyloid Peptides Studied with Atomistic Simulations.

    PubMed

    Carballo-Pacheco, Martín; Ismail, Ahmed E; Strodel, Birgit

    2015-07-30

    Amyloids are associated with diseases, including Alzheimer's, as well as functional roles such as storage of peptide hormones. It is still unclear what differences exist between aberrant and functional amyloids. However, it is known that soluble oligomers formed during amyloid aggregation are more toxic than the final fibrils. Here, we perform molecular dynamics simulations to study the aggregation of the amyloid-β peptide Aβ25-35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Although the three peptides have similar primary sequences, tachykinin peptides, in contrast to Aβ25-35, form nontoxic amyloids. Our simulations reveal that the charge of the C-terminus is essential to controlling the aggregation process. In particular, when the kassinin C-terminus is not amidated, the aggregation kinetics decreases considerably. In addition, we observe that the monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. PMID:26130191

  18. A Stable Mutant Predisposes Antibody Domains to Amyloid Formation through Specific Non-Native Interactions.

    PubMed

    Nokwe, Cardine N; Hora, Manuel; Zacharias, Martin; Yagi, Hisashi; Peschek, Jirka; Reif, Bernd; Goto, Yuji; Buchner, Johannes

    2016-03-27

    The aggregation of mostly antibody light chain variable (VL) domains into amyloid fibrils in various tissues is the main cause of death in systemic amyloid light chain amyloidosis. Point mutations within the domain are important to shift the VL into the fibrillar pathway, but why and how only some site-specific mutations achieve this still remains elusive. We show here that both destabilizing and surprisingly stable mutants readily predispose an amyloid-resistant VL domain to amyloid formation. The decreased thermodynamic stability of the destabilizing mutant results in the accumulation of non-native intermediates that readily populate the amyloid state. Interestingly, the stable mutants establish site-specific non-native interactions with especially nearby serine/threonine residues that unexpectedly do not affect the folding behavior of the VL domain but rather readily induce and stabilize the fibril structure, a previously unrecognized mechanism. These findings provide a new concept for the molecular mechanism of amyloid fibril formation. PMID:26827727

  19. Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer's disease.

    PubMed

    Beauquis, Juan; Vinuesa, Angeles; Pomilio, Carlos; Pavía, Patricio; Galván, Verónica; Saravia, Flavia

    2014-03-01

    In the context of Alzheimer's disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when amyloid deposition, inflammation and glial activation occur, but less attention has been directed to studying early brain and behavioral changes. Using an animal model of AD, the transgenic PDAPP-J20 mouse at 5 months of age, when no amyloid plaques are present and low cerebral levels of amyloid peptides are detectable, we found structural, morphological, and cellular alterations in the hippocampus. Young transgenic mice showed a reduced hippocampal volume with less number of pyramidal and granular neurons, which additionally exhibited cell atrophy. The neurogenic capability in this zone, measured as DCX+ cells, was strongly diminished and associated to alterations in cell maturity. A decrease in presynaptic synaptophysin optical density was detected in mossy fibers reaching CA3 subfield but not in Golgi stained- CA1 dendritic spine density. Employing confocal microscopy and accurate stereological tools we also found a reduction in the number of GFAP+ cells, along with decreased astrocyte complexity, suggesting a potential detriment of neural support. According with untimely neuroglial alterations, young PDAPP mice failed in the novel location recognition test, that depends on hippocampal function. Moreover, multivariate statistical analysis of the behavioral outcome in the open-field test evidenced an elevated anxiety score in Tg mice compared with age-matched control mice. In line with this, the transgenic group showed a higher number of c-Fos+ nuclei in central and basolateral amygdala, a result that supports the early involvement of the emotionality factor in AD pathology. Applying an integrative approach, this work focuses on early structural, morphological and functional changes and provides new and compelling evidence of behavioral alterations that precede manifest AD. PMID:24132937

  20. Focal cerebral ischaemia induces a decrease in activity and a shift in ouabain affinity of Na+, K+-ATPase isoforms without modifications in mRNA and protein expression.

    PubMed

    Jamme, I; Barbey, O; Trouvé, P; Charlemagne, D; Maixent, J M; MacKenzie, E T; Pellerin, L; Nouvelot, A

    1999-02-20

    In a mouse model of focal cerebral ischaemia, we observed after 1 h of ischaemia, that the total Na+, K+-ATPase activity was decreased by 39.4%, and then did not vary significantly up to 6 h post-occlusion. In the sham group, the dose-response curves for ouabain disclosed three inhibitory sites of low (LA), high (HA) and very high (VHA) affinity. In ischaemic animals, we detected the presence of only two inhibitory sites for ouabain. After 1 h of permanent occlusion, the first site exhibited a low affinity while the second site presented an affinity intermediate between those of HA and VHA sites, which evolved after 3 h and 6 h of occlusion towards that of the VHA site. The presence of only two ouabain sites for Na+, K+-ATPase after ischaemia could result from a change in ouabain affinity of both HA and VHA sites (alpha2 and alpha3 isoforms, respectively) to form a unique component. Irrespective of the duration of ischaemia, the smaller activity of this second site accounted entirely for the loss in total activity. Surprisingly, no modifications in protein and mRNA expression of any alpha or beta isoforms of the enzyme were observed, thus suggesting that ischaemia could induce intrinsic modifications of the Na+, K+-ATPase. PMID:10082868

  1. Asymmetries of amyloid-β burden and neuronal dysfunction are positively correlated in Alzheimer's disease.

    PubMed

    Frings, Lars; Hellwig, Sabine; Spehl, Timo S; Bormann, Tobias; Buchert, Ralph; Vach, Werner; Minkova, Lora; Heimbach, Bernhard; Klöppel, Stefan; Meyer, Philipp T

    2015-10-01

    Clinical Alzheimer's disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-β burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-β deposition in Alzheimer's disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimer's disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-β and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-β deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-β deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-β burden and hypometabolism than patients with predominant visuospatial impairment

  2. Increased cerebral vascular reactivity in the tau expressing rTg4510 mouse: evidence against the role of tau pathology to impair vascular health in Alzheimer's disease

    PubMed Central

    Wells, Jack A; Holmes, Holly E; O'Callaghan, James M; Colgan, Niall; Ismail, Ozama; Fisher, Elizabeth MC; Siow, Bernard; Murray, Tracey K; Schwarz, Adam J; O'Neill, Michael J; Collins, Emily C; Lythgoe, Mark F

    2015-01-01

    Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients. PMID:25515210

  3. Increased cerebral vascular reactivity in the tau expressing rTg4510 mouse: evidence against the role of tau pathology to impair vascular health in Alzheimer's disease.

    PubMed

    Wells, Jack A; Holmes, Holly E; O'Callaghan, James M; Colgan, Niall; Ismail, Ozama; Fisher, Elizabeth Mc; Siow, Bernard; Murray, Tracey K; Schwarz, Adam J; O'Neill, Michael J; Collins, Emily C; Lythgoe, Mark F

    2015-03-01

    Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients. PMID:25515210

  4. Molecular diagnosis of hereditary cystatin C amyloid angiopathy.

    PubMed

    Jonsdottir, S; Palsdottir, A

    1993-04-01

    Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disorder characterized by the deposition of amyloid in most investigated tissues. The main component of the amyloid deposits is a variant of the cysteine proteinase inhibitor cystatin C, and the most serious consequence of the disease is that amyloid deposition in the cerebral arteries leads to a massive brain hemorrhage and death before 40 years of age. HCCAA has been shown to be caused by a T-->A point mutation in the codon for leucine at position 68 in exon 2 of the cystatin C gene, which results in a leucine-->glutamine amino acid substitution in the cystatin C molecule. Since the HCCAA-causing mutation abolishes an AluI restriction site in the cystatin C gene, analysis of this AluI restriction fragment-length polymorphism (RFLP) enables simple and accurate molecular diagnosis of HCCAA. One hundred ninety-one individuals have now been screened for the HCCAA causing mutation, including a fetus for prenatal diagnosis. Thirty-six individuals belonging to nine Icelandic families have been found to have the mutation and it is highly probable that these families descend from a common ancestor. PMID:8097919

  5. Brain Endothelial Cells Produce Amyloid β from Amyloid Precursor Protein 770 and Preferentially Secrete the O-Glycosylated Form*

    PubMed Central

    Kitazume, Shinobu; Tachida, Yuriko; Kato, Masaki; Yamaguchi, Yoshiki; Honda, Takashi; Hashimoto, Yasuhiro; Wada, Yoshinao; Saito, Takashi; Iwata, Nobuhisa; Saido, Takaomi; Taniguchi, Naoyuki

    2010-01-01

    Deposition of amyloid β (Aβ) in the brain is closely associated with Alzheimer disease (AD). Aβ is generated from amyloid precursor protein (APP) by the actions of β- and γ-secretases. In addition to Aβ deposition in the brain parenchyma, deposition of Aβ in cerebral vessel walls, termed cerebral amyloid angiopathy, is observed in more than 80% of AD individuals. The mechanism for how Aβ accumulates in blood vessels remains largely unknown. In the present study, we show that brain endothelial cells expressed APP770, a differently spliced APP mRNA isoform from neuronal APP695, and produced Aβ40 and Aβ42. Furthermore, we found that the endothelial APP770 had sialylated core 1 type O-glycans. Interestingly, Ο-glycosylated APP770 was preferentially processed by both α- and β-cleavage and secreted into the media, suggesting that O-glycosylation and APP processing involved related pathways. By immunostaining human brain sections with an anti-APP770 antibody, we found that APP770 was expressed in vascular endothelial cells. Because we were able to detect O-glycosylated sAPP770β in human cerebrospinal fluid, this unique soluble APP770β has the potential to serve as a marker for cortical dementias such as AD and vascular dementia. PMID:20952385

  6. Houshiheisan compound prescription protects neurovascular units after cerebral ischemia.

    PubMed

    Wang, Haizheng; Wang, Lei; Zhang, Nan; Zhang, Qi; Zhao, Hui; Zhang, Qiuxia

    2014-04-01

    Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-β 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-β 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra. PMID:25206882

  7. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    SciTech Connect

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; Foster, Carmen M.; Kennel, Stephen J.; Wall, Jonathan S.

    2015-09-22

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  8. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    DOE PAGESBeta

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; et al

    2015-09-22

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presencemore » of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.« less

  9. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

    PubMed Central

    McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; Foster, Carmen M.; Kennel, Stephen J.; Wall, Jonathan S.

    2015-01-01

    Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils. PMID:26393799

  10. Amyloid-Associated Depression

    PubMed Central

    Sun, Xiaoyan; Steffens, David C.; Au, Rhoda; Folstein, Marshal; Summergrad, Paul; Yee, Jacqueline; Rosenberg, Irwin; Mwamburi, D. Mkaya; Qiu, Wei Qiao

    2010-01-01

    Context A high ratio of plasma amyloid-β peptide 40 (Aβ40) toAβ42, determined by both high Aβ40 and low Aβ42 levels, increases the risk of Alzheimer disease. In a previous study, we reported that depression is also associated with low plasma Aβ42 levels in the elderly population. Objective To characterize plasma Aβ40:Aβ42 ratio and cognitive function in elderly individuals with and without depression. Design Cross-sectional study. Setting Homecare agencies. Participants A total of 995 homebound elderly individuals of whom 348 were defined as depressed by a Center for Epidemiological Studies Depression score of 16 or greater. Main Outcome Measures Cognitive domains of memory, language, executive, and visuospatial functions according to levels of plasma Aβ40 and Aβ42 peptides. Results Subjects with depression had lower plasma Aβ42 levels (median, 14.1 vs 19.2 pg/mL; P = .006) and a higher plasma Aβ40:Aβ42 ratio (median, 8.9 vs 6.4; P < .001) than did those without depression in the absence of cardiovascular disease and antidepressant use. The interaction between depression and plasma Aβ40:Aβ42 ratio was associated with lower memory score (β = −1.9, SE = 0.7, P = .006) after adjusting for potentially confounders. Relative to those without depression, “amyloid-associated depression,” defined by presence of depression and a high plasma Aβ40:Aβ42 ratio, was associated with greater impairment in memory, visuospatial ability, and executive function; in contrast, nonamyloid depression was not associated with memory impairment but with other cognitive disabilities. Conclusion Amyloid-associated depression may define a subtype of depression representing a prodromal manifestation of Alzheimer disease. PMID:18458206

  11. Towards a Pharmacophore for Amyloid

    SciTech Connect

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds

  12. Cerebral palsy.

    PubMed

    Wimalasundera, Neil; Stevenson, Valerie L

    2016-06-01

    Cerebral palsy has always been known as a disorder of movement and posture resulting from a non-progressive injury to the developing brain; however, more recent definitions allow clinicians to appreciate more than just the movement disorder. Accurate classification of cerebral palsy into distribution, motor type and functional level has advanced research. It also facilitates appropriate targeting of interventions to functional level and more accurate prognosis prediction. The prevalence of cerebral palsy remains fairly static at 2-3 per 1000 live births but there have been some changes in trends for specific causal groups. Interventions for cerebral palsy have historically been medical and physically focused, often with limited evidence to support their efficacy. The use of more appropriate outcome measures encompassing quality of life and participation is helping to deliver treatments which are more meaningful for people with cerebral palsy and their carers. PMID:26837375

  13. Decreased Plasma Aβ in Hyperlipidemic APPSL Transgenic Mice Is Associated with BBB Dysfunction

    PubMed Central

    Löffler, Tina; Flunkert, Stefanie; Temmel, Magdalena; Hutter-Paier, Birgit

    2016-01-01

    Besides the continued focus on Aβ and Tau in Alzheimer's disease (AD), it is increasingly evident that other pathologic characteristics, such as vascular alterations or inflammation, are associated with AD. Whether these changes are an initial cause for the onset of AD or occur as a result of the disease in late stages is still under debate. In the present study, the impact of the high-fat diet (HFD) induced vascular risk factor hyperlipidemia on Aβ levels and clearance as well as cerebral vasculature and blood-brain barrier (BBB) integrity was examined in mice. For this purpose, human APP transgenic (APPSL) and wildtype (WT) mice were fed a HFD for 12 weeks. Plasma and tissues were subsequently investigated for Aβ distribution and concentrations of several vascular markers. Decreased plasma Aβ together with increased levels of insoluble Aβ and amyloid plaques in the brains of HFD fed APPSL mice point toward impaired Aβ clearance due to HFD. Additionally, HFD induced manifold alterations in the cerebral vasculature and BBB integrity exclusively in human APP overexpressing mice but not in wildtype mice. Therefore, HFD appears to enhance Aβ dependent vascular/BBB dysfunction in combination with an increased proportion of cerebral to plasma Aβ in APPSL mice. PMID:27313503

  14. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

    PubMed

    Mattsson, Niklas; Insel, Philip S; Donohue, Michael; Landau, Susan; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W

    2015-03-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  15. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease

    PubMed Central

    Insel, Philip S.; Donohue, Michael; Landau, Susan; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W.

    2015-01-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  16. Nanomaterials: amyloids reflect their brighter side

    PubMed Central

    Mankar, Shruti; Anoop, A.; Sen, Shamik; Maji, Samir K.

    2011-01-01

    Amyloid fibrils belong to the group of ordered nanostructures that are self-assembled from a wide range of polypeptides/proteins. Amyloids are highly rigid structures possessing a high mechanical strength. Although amyloids have been implicated in the pathogenesis of several human diseases, growing evidence indicates that amyloids may also perform native functions in host organisms. Discovery of such amyloids, referred to as functional amyloids, highlight their possible use in designing novel nanostructure materials. This review summarizes recent advances in the application of amyloids for the development of nanomaterials and prospective applications of such materials in nanotechnology and biomedicine. PMID:22110868

  17. Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

    PubMed Central

    Keaney, James; Walsh, Dominic M.; O’Malley, Tiernan; Hudson, Natalie; Crosbie, Darragh E.; Loftus, Teresa; Sheehan, Florike; McDaid, Jacqueline; Humphries, Marian M.; Callanan, John J.; Brett, Francesca M.; Farrell, Michael A.; Humphries, Peter; Campbell, Matthew

    2015-01-01

    The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain. PMID:26491725

  18. Post-mortem assessment of hypoperfusion of cerebral cortex in Alzheimer's disease and vascular dementia.

    PubMed

    Thomas, Taya; Miners, Scott; Love, Seth

    2015-04-01

    Perfusion is reduced in the cerebral neocortex in Alzheimer's disease. We have explored some of the mechanisms, by measurement of perfusion-sensitive and disease-related proteins in post-mortem tissue from Alzheimer's disease, vascular dementia and age-matched control brains. To distinguish physiological from pathological reduction in perfusion (i.e. reduction exceeding the decline in metabolic demand), we measured the concentration of vascular endothelial growth factor (VEGF), a protein induced under conditions of tissue hypoxia through the actions of hypoxia-inducible factors, and the myelin associated glycoprotein to proteolipid protein 1 (MAG:PLP1) ratio, which declines in chronically hypoperfused brain tissue. To evaluate possible mechanisms of hypoperfusion, we also measured the levels of amyloid-β40, amyloid-β42, von Willebrand factor (VWF; a measure of microvascular density) and the potent vasoconstrictor endothelin 1 (EDN1); we assayed the activity of angiotensin I converting enzyme (ACE), which catalyses the production of another potent vasoconstrictor, angiotensin II; and we scored the severity of arteriolosclerotic small vessel disease and cerebral amyloid angiopathy, and determined the Braak tangle stage. VEGF was markedly increased in frontal and parahippocampal cortex in Alzheimer's disease but only slightly and not significantly in vascular dementia. In frontal cortex the MAG:PLP1 ratio was significantly reduced in Alzheimer's disease and even more so in vascular dementia. VEGF but not MAG:PLP1 increased with Alzheimer's disease severity, as measured by Braak tangle stage, and correlated with amyloid-β42 and amyloid-β42: amyloid-β40 but not amyloid-β40. Although MAG:PLP1 tended to be lowest in cortex from patients with severe small vessel disease or cerebral amyloid angiopathy, neither VEGF nor MAG:PLP1 correlated significantly with the severity of structural vascular pathology (small vessel disease, cerebral amyloid angiopathy or VWF

  19. Cerebral palsy.

    PubMed

    Graham, H Kerr; Rosenbaum, Peter; Paneth, Nigel; Dan, Bernard; Lin, Jean-Pierre; Damiano, Diane L; Becher, Jules G; Gaebler-Spira, Deborah; Colver, Allan; Reddihough, Dinah S; Crompton, Kylie E; Lieber, Richard L

    2016-01-01

    Cerebral palsy is the most common cause of childhood-onset, lifelong physical disability in most countries, affecting about 1 in 500 neonates with an estimated prevalence of 17 million people worldwide. Cerebral palsy is not a disease entity in the traditional sense but a clinical description of children who share features of a non-progressive brain injury or lesion acquired during the antenatal, perinatal or early postnatal period. The clinical manifestations of cerebral palsy vary greatly in the type of movement disorder, the degree of functional ability and limitation and the affected parts of the body. There is currently no cure, but progress is being made in both the prevention and the amelioration of the brain injury. For example, administration of magnesium sulfate during premature labour and cooling of high-risk infants can reduce the rate and severity of cerebral palsy. Although the disorder affects individuals throughout their lifetime, most cerebral palsy research efforts and management strategies currently focus on the needs of children. Clinical management of children with cerebral palsy is directed towards maximizing function and participation in activities and minimizing the effects of the factors that can make the condition worse, such as epilepsy, feeding challenges, hip dislocation and scoliosis. These management strategies include enhancing neurological function during early development; managing medical co-morbidities, weakness and hypertonia; using rehabilitation technologies to enhance motor function; and preventing secondary musculoskeletal problems. Meeting the needs of people with cerebral palsy in resource-poor settings is particularly challenging. PMID:27188686

  20. Beta-amyloid fibrils of Alzheimer's disease: pathologically altered, basement membrane-associated microfibrils?

    PubMed

    Inoue, S; Kisilevsky, R

    2001-01-01

    Beta amyloid fibrils were examined in situ in the cerebral cortex of brains from patients with Alzheimer's disease using high resolution ultrastructural and immunohistochemical techniques. The main body of the fibril was identical with that of microfibrils and was made up of a core containing amyloid P component (AP), and a surface layer. Beta amyloid protein (Abeta) in the form of 1 nm wide flexible filaments was associated with the external surface of the microfibril. In cerebrovascular amyloid angiopathy the fibrils were formed at the outer surface of the vascular basement membrane. Overproduction of microfibrils has been reported at the basement membrane of "leaky" capillaries including the glomerular capillary in disease or leaky alveolar-capillary walls of normal lungs. Similarly, in Alzheimer's disease overproduction of microfibril-like beta amyloid fibrils in amyloid angiopathy coincided with breakdown of the blood-brain barrier of the cerebromicrovasculature. Thus, in the above three locations, the presence of abundant microfibrils, or microfibril-like structures, may be related to plasma which leaks out of the circulation into the adjoining vascular basement membrane. AP is an essential constituent of microfibrils and since the only site where AP is available in the cerebral cortex is in leaky microvasculature, a chronic, steady supply of AP into perivascular areas may be the cause of overproduction of microfibrils. Brain "microfibrils" may further be altered pathologically into beta amyloid fibrils by the addition of Abeta. The origin of the fibrils in senile plaques may also be the microvasculature since in the area of the plaques no source of AP is apparent. PMID:11730002

  1. Imbalance in Fatty-Acid-Chain Length of Gangliosides Triggers Alzheimer Amyloid Deposition in the Precuneus

    PubMed Central

    Oikawa, Naoto; Matsubara, Teruhiko; Fukuda, Ryoto; Yasumori, Hanaki; Hatsuta, Hiroyuki; Murayama, Shigeo; Sato, Toshinori; Suzuki, Akemi; Yanagisawa, Katsuhiko

    2015-01-01

    Amyloid deposition, a crucial event of Alzheimer’s disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition. PMID:25798597

  2. [Clinical relevance of cerebral microbleeds--update].

    PubMed

    Yakushjii, Yusuke; Tanaka, Jun; Hara, Hideo

    2016-04-01

    Cerebral microbleeds (CMBs) on paramagnetic-sensitive magnetic resonance sequences correspond pathologically to clusters of hemosiderin-laden macrophages and have emerged as an important new imaging marker of cerebral small vessel disease (SVD), including intracerebral hemorrhage (ICH). The prevalence of CMBs varies according to the specific disease settings (stroke subtypes and demented disorders) and is highest in ICH patients. The associations of CMBs with aging, hypertension and apolipoprotein E genotype are consistent with the two major underlying pathogenesis of CMBs: hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). The distributional patterns of CMBs might help us understand the predominant SVD pathogenesis of the brain; the strictly lobar type of CMBs often reflects the presence of advanced CAA, while the other types of CMBs, such as "deep or infratentorial CMBs", including the mixed type, are strongly associated with hypertension. PMID:27333747

  3. Cerebral Palsy

    MedlinePlus

    ... Español (Spanish) Recommend on Facebook Tweet Share Compartir Cerebral palsy (CP) is a group of disorders that affect a ... ability to move and maintain balance and posture. CP is the most common motor disability in childhood. ...

  4. Cerebral Arteriosclerosis

    MedlinePlus

    ... Cerebral arteriosclerosis is the result of thickening and hardening of the walls of the arteries in the ... cause an ischemic stroke. When the thickening and hardening is uneven, arterial walls can develop bulges (called ...

  5. Cerebral angiography

    MedlinePlus

    ... Cerebral angiography is done in the hospital or radiology center. You lie on an x-ray table. ... be done in preparation for medical treatment (interventional radiology procedures) by way of certain blood vessels. What ...

  6. Cognitive decline and brain volume loss are signatures of cerebral Aβ deposition identified with PIB

    PubMed Central

    Storandt, Martha; Mintun, Mark A.; Head, Denise; Morris, John C.

    2009-01-01

    Objective To examine the relation of amyloid-beta (Aβ) levels in cerebral cortex with structural brain integrity and cognitive performance in older people with a Clinical Dementia Rating (CDR) of 0 (cognitively normal). Methods The relations between mean cortical [11C] PIB binding potential values, proportional to the density of fibrillar Aβ binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal (up to 19 years) cognitive performance in multiple domains were examined in 135 CDR 0 individuals aged 65 to 88 years. Results Elevated cerebral Aβ levels, in some cases comparable to that seen in individuals with Alzheimer's disease, were observed in 29 CDR 0 individuals. Significantly smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate were observed in these CDR 0 individuals with elevated Aβ levels. Concurrent cognitive performance was unrelated to Aβ levels but was related to regional brain volumes with the exception of caudate. Longitudinal cognitive decline was associated with elevated Aβ levels and decreased hippocampal volume. Decline was not limited to episodic memory but included working memory and visuospatial abilities as well. Interpretation [11C] PIB, an in vivo measure of cerebral amyloidosis, is associated with regionally specific brain atrophy cross-sectionally and a pattern of longitudinal cognitive decline in multiple cognitive domains that occurs prior to the clinical diagnosis of Alzheimer' disease. These findings contribute to the understanding of the cognitive and structural consequences of Aβ levels in CDR 0 older adults. PMID:20008651

  7. Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals

    PubMed Central

    Gregg, Nicholas M.; Kim, Albert E.; Gurol, M. Edip; Lopez, Oscar L.; Aizenstein, Howard J.; Price, Julie C.; Mathis, Chester A.; James, Jeffrey A.; Snitz, Beth E.; Cohen, Ann D.; Kamboh, M. Ilyas; Minhas, Davneet; Weissfeld, Lisa A.; Tamburo, Erica L.; Klunk, William E.

    2016-01-01

    IMPORTANCE Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. OBJECTIVE To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. INTERVENTIONS 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. MAIN OUTCOMES AND MEASURES Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. RESULTS The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF,

  8. Pituicytoma with gelsolin amyloid deposition.

    PubMed

    Ida, Cristiane M; Yan, Xiaoling; Jentoft, Mark E; Kip, N Sertac; Scheithauer, Bernd W; Morris, Jonathan M; Dogan, Ahmet; Parisi, Joseph E; Kovacs, Kalman

    2013-09-01

    Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition. PMID:23817895

  9. Deformation behavior and mechanical properties of amyloid protein nanowires.

    PubMed

    Solar, Max; Buehler, Markus J

    2013-03-01

    Amyloid fibrils are most often associated with their pathological role in diseases like Alzheimer's disease and Parkinson's disease, but they are now increasingly being considered for uses in functional engineering materials. They are among the stiffest protein fibers known but they are also rather brittle, and it is unclear how this combination of properties affects the behavior of amyloid structures at larger length scales, such as in films, wires or plaques. Using a coarse-grained model for amyloid fibrils, we study the mechanical response of amyloid nanowires and examine fundamental mechanical properties, including mechanisms of deformation and failure under tensile loading. We also explore the effect of varying the breaking strain and adhesion strength of the constituent amyloid fibrils on the properties of the larger structure. We find that deformation in the nanowires is controlled by a combination of fibril sliding and fibril failure and that there exists a transition from brittle to ductile behavior by either increasing the fibril failure strain or decreasing the strength of adhesion between fibrils. Furthermore, our results reveal that the mechanical properties of the nanowires are quite sensitive to changes in the properties of the individual fibrils, and the larger scale structures are found to be more mechanically robust than the constituent fibrils, for all cases considered. More broadly, this work demonstrates the promise of utilizing self-assembled biological building blocks in the development of hierarchical nanomaterials. PMID:23290516

  10. Unzipping a Functional Microbial Amyloid

    PubMed Central

    Alsteens, David; Ramsook, Caleen B.; Lipke, Peter N.; Dufrêne, Yves F.

    2012-01-01

    Bacterial and fungal species produce some of the best-characterized functional amyloids, i.e. extracellular fibres that play key roles in mediating adhesion and biofilm formation. Yet, the molecular details underlying their mechanical strength remain poorly understood. Here, we use single-molecule atomic force microscopy to measure the mechanical properties of amyloids formed by Als cell adhesion proteins from the pathogen Candida albicans. We show that stretching Als proteins through their amyloid sequence yields characteristic force signatures corresponding to the mechanical unzipping of β-sheet interactions formed between surfacearrayed Als proteins. The unzipping probability increases with contact time, reflecting the time necessary for optimal inter β-strand associations. These results demonstrate that amyloid interactions provide cohesive strength to a major adhesion protein from a microbial pathogen, thereby strengthening cell adhesion. We suggest that such functional amyloids may represent a generic mechanism for providing mechanical strength to cell adhesion proteins. In nanotechnology, these single-molecule manipulation experiments provide new opportunities to understand the molecular mechanisms driving the cohesion of functional amyloid-based nanostructures. PMID:22924880

  11. Absence of beta-amyloid in cortical cataracts of donors with and without Alzheimer's disease.

    PubMed

    Michael, Ralph; Rosandić, Jurja; Montenegro, Gustavo A; Lobato, Elvira; Tresserra, Francisco; Barraquer, Rafael I; Vrensen, Gijs F J M

    2013-01-01

    Eye lenses from human donors with and without Alzheimer's disease (AD) were studied to evaluate the presence of amyloid in cortical cataract. We obtained 39 lenses from 21 postmortem donors with AD and 15 lenses from age-matched controls provided by the Banco de Ojos para Tratamientos de la Ceguera (Barcelona, Spain). For 17 donors, AD was clinically diagnosed by general physicians and for 4 donors the AD diagnosis was neuropathologically confirmed. Of the 21 donors with AD, 6 had pronounced bilateral cortical lens opacities and 15 only minor or no cortical opacities. As controls, 7 donors with pronounced cortical opacities and 8 donors with almost transparent lenses were selected. All lenses were photographed in a dark field stereomicroscope. Histological sections were analyzed using a standard and a more sensitive Congo red protocol, thioflavin staining and beta-amyloid immunohistochemistry. Brain tissue from two donors, one with cerebral amyloid angiopathy and another with advanced AD-related changes and one cornea with lattice dystrophy were used as positive controls for the staining techniques. Thioflavin, standard and modified Congo red staining were positive in the control brain tissues and in the dystrophic cornea. Beta-amyloid immunohistochemistry was positive in the brain tissues but not in the cornea sample. Lenses from control and AD donors were, without exception, negative after Congo red, thioflavin, and beta-amyloid immunohistochemical staining. The results of the positive control tissues correspond well with known observations in AD, amyloid angiopathy and corneas with lattice dystrophy. The absence of staining in AD and control lenses with the techniques employed lead us to conclude that there is no beta-amyloid in lenses from donors with AD or in control cortical cataracts. The inconsistency with previous studies of Goldstein et al. (2003) and Moncaster et al. (2010), both of which demonstrated positive Congo red, thioflavin, and beta-amyloid

  12. Cerebral Palsy (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Cerebral Palsy KidsHealth > For Parents > Cerebral Palsy Print A A ... kids who are living with the condition. About Cerebral Palsy Cerebral palsy is one of the most common ...

  13. Cerebral palsy - resources

    MedlinePlus

    Resources - cerebral palsy ... The following organizations are good resources for information on cerebral palsy : National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/cerebral_palsy/cerebral_palsy. ...

  14. Finding of vascular amyloid TTR in inferior nasal concha in a patient with FAP TTRVal30Met.

    PubMed

    Munar-Ques, Miguel; Martinez-Nadal, Jacinto; Torres-Rovira, Jose Juan; Sole, Manel; Zabay-Becerril, Jose Maria; Mulet-Ferrer, Juana Maria

    2008-12-01

    We report the case of a female patient with familial amyloid polyneuropathy (FAP) who demonstrated TTR amyloid deposition in the inferior nasal conchal vessels. To our knowledge this location has not been described previously in FAP; in addition, it was detected in a patient who had undergone successful liver transplantation (LTX) 4 years earlier. The amyloid deposition was found incidentally during examination of a right nasal obstruction caused by a nonspecific inflammatory polyp. Small focal deposits of amyloid TTR were observed on deep thick walled vessels, contrasting with the massive deposition reported in neoformed vessels in amyloidomas. This amyloid was clearly deposited between the onset of FAP and LTX and had probably decreased since the graft. If amyloid deposition is frequent in inferior nasal concha in FAP, this location could be a suitable biopsy site. PMID:19065300

  15. Intravital imaging of amyloid plaques in a transgenic mouse model using optical-resolution photoacoustic microscopy

    PubMed Central

    Hu, Song; Yan, Ping; Maslov, Konstantin; Lee, Jin-Moo; Wang, Lihong V.

    2010-01-01

    We report optical-resolution photoacoustic microscopy (OR-PAM) for in vivo imaging of amyloid plaques in an Alzheimer’s disease mouse model. Validation using conventional fluorescence microscopy and multiphoton microscopy shows that OR-PAM has sufficient sensitivity and spatial resolution to identify amyloid plaques in living brains. In addition, with dual-wavelength OR-PAM, the three-dimensional morphology of amyloid plaques and the surrounding microvasculature are imaged simultaneously through a cranial window without angiographic contrast agents. OR-PAM, capable of providing both exogenous molecular contrast and endogenous hemoglobin contrast, has the potential to serve as a new technology for in vivo microscopic observations of cerebral plaque deposits. PMID:20016651

  16. Polyfluorinated bis-styrylbenzenes as amyloid-β plaque binding ligands.

    PubMed

    Nabuurs, Rob J A; Kapoerchan, Varsha V; Metaxas, Athanasios; de Jongh, Sanne; de Backer, Maaike; Welling, Mick M; Jiskoot, Wim; Windhorst, Albert D; Overkleeft, Hermen S; van Buchem, Mark A; Overhand, Mark; van der Weerd, Louise

    2014-04-15

    Detection of cerebral β-amyloid (Aβ) by targeted contrast agents remains of great interest to aid the in vivo diagnosis of Alzheimer's disease (AD). Bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. To further explore their potency as (19)F MRI contrast agents we synthetized several novel fluorinated bis-styrylbenzenes and studied their fluorescent properties and amyloid-β binding characteristics. The compounds showed a high affinity for Aβ plaques on murine and human brain sections. Interestingly, competitive binding experiments demonstrated that they bound to a different binding site than chrysamine G. Despite their high logP values, many bis-styrylbenzenes were able to enter the brain and label murine amyloid in vivo. Unfortunately initial post-mortem (19)F NMR studies showed that these compounds as yet do not warrant further MRI studies due to the reduction of the (19)F signal in the environment of the brain. PMID:24657049

  17. Amyloid Beta1–42 and the Phoshorylated Tau Threonine 231 in Brains of Aged Cynomolgus Monkeys (Macaca fascicularis)

    PubMed Central

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin; Schapiro, Steven J.; Kalliokoski, Otto; Kristianingrum, Yuli P.; Handaryani, Ekowati; Hau, Jann

    2014-01-01

    Pathological hallmarks indicative of Alzheimer’s disease (AD), which are the plaques of amyloid beta1–42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1–42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject – with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1–42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease. PMID:25426069

  18. Prevalence of Amyloid PET Positivity in Dementia Syndromes

    PubMed Central

    Ossenkoppele, Rik; Jansen, Willemijn J.; Rabinovici, Gil D.; Knol, Dirk L.; van der Flier, Wiesje M.; van Berckel, Bart N. M.; Scheltens, Philip; Visser, Pieter Jelle

    2015-01-01

    IMPORTANCE Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non–AD dementia. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. DATA EXTRACTION AND SYNTHESIS Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non–AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method. RESULTS The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers(86%[95%CI,73%–94%]at 50 years to 68% [95% CI,57%–77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%–99%] at 50 years to 90% [95% CI, 83%–94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non–AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership. Total ParticipantsAmyloid Positivity, % (95% CI) Age 60 yAge 80

  19. Proteomic Screening for Amyloid Proteins

    PubMed Central

    Nizhnikov, Anton A.; Alexandrov, Alexander I.; Ryzhova, Tatyana A.; Mitkevich, Olga V.; Dergalev, Alexander A.; Ter-Avanesyan, Michael D.; Galkin, Alexey P.

    2014-01-01

    Despite extensive study, progress in elucidation of biological functions of amyloids and their role in pathology is largely restrained due to the lack of universal and reliable biochemical methods for their discovery. All biochemical methods developed so far allowed only identification of glutamine/asparagine-rich amyloid-forming proteins or proteins comprising amyloids that form large deposits. In this article we present a proteomic approach which may enable identification of a broad range of amyloid-forming proteins independently of specific features of their sequences or levels of expression. This approach is based on the isolation of protein fractions enriched with amyloid aggregates via sedimentation by ultracentrifugation in the presence of strong ionic detergents, such as sarkosyl or SDS. Sedimented proteins are then separated either by 2D difference gel electrophoresis or by SDS-PAGE, if they are insoluble in the buffer used for 2D difference gel electrophoresis, after which they are identified by mass-spectrometry. We validated this approach by detection of known yeast prions and mammalian proteins with established capacity for amyloid formation and also revealed yeast proteins forming detergent-insoluble aggregates in the presence of human huntingtin with expanded polyglutamine domain. Notably, with one exception, all these proteins contained glutamine/asparagine-rich stretches suggesting that their aggregates arose due to polymerization cross-seeding by human huntingtin. Importantly, though the approach was developed in a yeast model, it can easily be applied to any organism thus representing an efficient and universal tool for screening for amyloid proteins. PMID:25549323

  20. Porcine prion protein amyloid

    PubMed Central

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    ABSTRACT Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions. PMID:26218890

  1. Cerebral Microcirculation during Experimental Normovolaemic Anemia

    PubMed Central

    Bellapart, Judith; Cuthbertson, Kylie; Dunster, Kimble; Diab, Sara; Platts, David G.; Raffel, O. Christopher; Gabrielian, Levon; Barnett, Adrian; Paratz, Jenifer; Boots, Rob; Fraser, John F.

    2016-01-01

    Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain. PMID:26869986

  2. Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase.

    PubMed

    Potter, K J; Werner, I; Denroche, H C; Montane, J; Plesner, A; Chen, Y; Lei, D; Soukhatcheva, G; Warnock, G L; Oberholzer, J; Fraser, P E; Verchere, C B

    2015-06-01

    Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function. PMID:25833002

  3. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.

    PubMed

    Casarejos, Maria J; Perucho, Juan; Gomez, Ana; Muñoz, Maria P; Fernandez-Estevez, Marian; Sagredo, Onintza; Fernandez Ruiz, Javier; Guzman, Manuel; de Yebenes, Justo Garcia; Mena, Maria A

    2013-01-01

    Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders. PMID:23478312

  4. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum

    PubMed Central

    Lowe, Val J.; Graff-Radford, Neill R.; Liesinger, Amanda M.; Cannon, Ashley; Przybelski, Scott A.; Rawal, Bhupendra; Parisi, Joseph E.; Petersen, Ronald C.; Kantarci, Kejal; Ross, Owen A.; Duara, Ranjan; Knopman, David S.; Jack, Clifford R.; Dickson, Dennis W.

    2015-01-01

    Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer’s disease, was incorporated into the latest National Institute of Ageing – Alzheimer’s Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer’s disease dementia published by the National Institute of Ageing – Alzheimer’s Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem 11C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of 11C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. 11C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical 11C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer’s disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer’s disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted 11C-Pittsburgh compound

  5. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum.

    PubMed

    Murray, Melissa E; Lowe, Val J; Graff-Radford, Neill R; Liesinger, Amanda M; Cannon, Ashley; Przybelski, Scott A; Rawal, Bhupendra; Parisi, Joseph E; Petersen, Ronald C; Kantarci, Kejal; Ross, Owen A; Duara, Ranjan; Knopman, David S; Jack, Clifford R; Dickson, Dennis W

    2015-05-01

    Thal amyloid phase, which describes the pattern of progressive amyloid-β plaque deposition in Alzheimer's disease, was incorporated into the latest National Institute of Ageing - Alzheimer's Association neuropathologic assessment guidelines. Amyloid biomarkers (positron emission tomography and cerebrospinal fluid) were included in clinical diagnostic guidelines for Alzheimer's disease dementia published by the National Institute of Ageing - Alzheimer's Association and the International Work group. Our first goal was to evaluate the correspondence of Thal amyloid phase to Braak tangle stage and ante-mortem clinical characteristics in a large autopsy cohort. Second, we examined the relevance of Thal amyloid phase in a prospectively-followed autopsied cohort who underwent ante-mortem (11)C-Pittsburgh compound B imaging; using the large autopsy cohort to broaden our perspective of (11)C-Pittsburgh compound B results. The Mayo Clinic Jacksonville Brain Bank case series (n = 3618) was selected regardless of ante-mortem clinical diagnosis and neuropathologic co-morbidities, and all assigned Thal amyloid phase and Braak tangle stage using thioflavin-S fluorescent microscopy. (11)C-Pittsburgh compound B studies from Mayo Clinic Rochester were available for 35 participants scanned within 2 years of death. Cortical (11)C-Pittsburgh compound B values were calculated as a standard uptake value ratio normalized to cerebellum grey/white matter. In the high likelihood Alzheimer's disease brain bank cohort (n = 1375), cases with lower Thal amyloid phases were older at death, had a lower Braak tangle stage, and were less frequently APOE-ε4 positive. Regression modelling in these Alzheimer's disease cases, showed that Braak tangle stage, but not Thal amyloid phase predicted age at onset, disease duration, and final Mini-Mental State Examination score. In contrast, Thal amyloid phase, but not Braak tangle stage or cerebral amyloid angiopathy predicted (11)C-Pittsburgh compound B

  6. Template-directed deposition of amyloid

    NASA Astrophysics Data System (ADS)

    Ha, Chanki

    The formation of amyloid plaques in tissue is a pathological feature of many neurodegenerative diseases. Amyloid deposition, the process of amyloid plaque growth by the association of individual soluble amyloid molecules with a pre-existing amyloid template (i.e. plaque), is known to be critical for amyloid formation in vivo. In order to characterize amyloid deposition, we developed novel, synthetic amyloid templates like amyloid plaques in the human Alzheimer's brain by attaching amyloid seeds covalently onto an N-hydroxysuccinimide-activated surface. Amyloid plaques with a characteristic beta-sheet structure formed through a conformational rearrangement of soluble insulin or Abeta monomers upon interaction with the template. The amyloid deposition rate followed saturation kinetics with respect to insulin concentration in the solution. According to visualization of temporal evolution of Abeta plaque deposition on a template, it was found that mature amyloid plaques serve as a sink of soluble Abeta in a solution as well as a reservoir of small aggregates such as oligomers and protofibrils. Quantitative analysis of seeding efficiencies of three different Abeta species revealed that oligomeric forms of Abeta act more efficiently as seeds than monomers or fibrils do. Furthermore, studies on the interaction between Abeta40 and 42 showed an important role of Abeta42 in amyloid deposition. A slightly acidic condition was found to be unfavorable for amyloid plaque formation. Effects of metal ions on amyloid deposition indicated that Fe3+, but not Cu3 and Zn2+, is important for the deposition of amyloid plaques. The binding of Fe3+ to Abeta42 peptide was confirmed by using SIMS analysis. Zn2+ induced nonfibrillar amorphous aggregates, but the release of Zn2+ from Abeta42 deposits by Fe3+ triggered the formation of amyloid fibers. Effects or metal ion chelators such as ethylenediamine tetraacetic acid, deferoxamine, and clioquinol on amyloid deposition were tested to

  7. Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis.

    PubMed

    Masliah, E; Raber, J; Alford, M; Mallory, M; Mattson, M P; Yang, D; Wong, D; Mucke, L

    1998-05-15

    Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission. PMID:9575214

  8. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission.

    PubMed

    Ovsepian, Saak V; O'Leary, Valerie B; Zaborszky, Laszlo

    2016-06-01

    Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID:26002948

  9. Cholinergic Mechanisms in the Cerebral Cortex: Beyond Synaptic Transmission

    PubMed Central

    Ovsepian, Saak V.; O'Leary, Valerie B.; Zaborszky, Laszlo

    2015-01-01

    Functional overviews of cholinergic mechanisms in the cerebral cortex have traditionally focused on the release of acetylcholine with modulator and transmitter effects. Recently, however, data have emerged that extend the role of acetylcholine and cholinergic innervations to a range of housekeeping and metabolic functions. These include regulation of amyloid precursor protein (APP) processing with production of amyloid β (Aβ) and other APP fragments and control of the phosphorylation of microtubule-associated protein (MAP) tau. Evidence has been also presented for receptor-ligand like interactions of cholinergic receptors with soluble Aβ peptide and MAP tau, with modulator and signaling effects. Moreover, high-affinity binding of Aβ to the neurotrophin receptor p75 (p75NTR) enriched in basalo-cortical cholinergic projections has been implicated in clearance of Aβ and nucleation of amyloid plaques. Here, we critically evaluate these unorthodox cholinergic mechanisms and discuss their role in neuronal physiology and the biology of Alzheimer's disease. PMID:26002948

  10. White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly

    PubMed Central

    Kantarci, Kejal; Schwarz, Christopher G.; Reid, Robert; Przybelski, Scott A.; Lesnick, Timothy; Zuk, Samantha M.; Senjem, Matthew L.; Gunter, Jeffrey L.; Lowe, Val; Machulda, Mary M.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.

    2016-01-01

    Importance Pathophysiologic mechanisms leading to loss of white matter (WM) integrity and the temporal positioning of biomarkers of WM integrity relative to the biomarkers of gray matter (GM) neurodegeneration and amyloid load in the course of AD are poorly understood. Objective To investigate the effects of Alzheimer’s disease (AD)-related GM neurodegeneration and high β-amyloid on white matter (WM) microstructure in non-demented older adults. Design Longitudinal cohort study Setting Population-based Mayo Clinic Study of Aging. Participants Participants (n=701) with MRI/DTI and PET studies diagnosed as cognitively normal (CN; n=570) or mild cognitive impairment (MCI; n=131) were included. CN and MCI subjects were divided into biomarker-negative, amyloid- positive only, neurodegeneration- positive only, and amyloid plus neurodegeneration-positive groups based on their amyloid load on 11C-Pittsburgh compound-B PET, AD hypometabolic pattern on 18F-fluorodeoxyglucose PET and/or hippocampal atrophy on MRI. Main Outcome Measure Fractional anisotrophy (FA) from diffusion tensor imaging (DTI) Results No FA alterations were observed in biomarker-negative MCI, and amyloid-positive only CN and MCI groups. Conversely, neurodegeneration-positive only and amyloid plus neurodegeneration- positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (Rho=0.38; p<0.001). Patients with MCI had more extensive WM involvement than CN subjects, and greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group. Conclusions and Relevance High amyloid load does not influence DTI-based measures of WM integrity in the absence of co-existent GM neurodegeneration in non-demented older adults. PMID:25347157

  11. Glucose regulates amyloid β production via AMPK.

    PubMed

    Yang, Ting-Ting; Shih, Yao-Shan; Chen, Yun-Wen; Kuo, Yu-Min; Lee, Chu-Wan

    2015-10-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly. Accumulation of Aβ peptides in the brain has been suggested as the cause of AD (amyloid cascade hypothesis); however, the mechanism for the abnormal accumulation of Aβ in the brains of AD patients remains unclear. A plethora of evidence has emerged to support a link between metabolic disorders and AD. This study was designed to examine the relationship between energy status and Aβ production. Neuro 2a neuroblastoma cells overexpressing human amyloid precursor protein 695 (APP cells) were cultured in media containing different concentrations of glucose and agonist or antagonist of AMP-activated-protein-kinase (AMPK), a metabolic master sensor. The results showed that concentrations of glucose in the culture media were negatively associated with the activation statuses of AMPK in APP cells, but positively correlated with the levels of secreted Aβ. Modulating AMPK activities affected the production of Aβ. If APP cells were cultured in high glucose medium (i.e., AMPK was inactive), stimulation of AMPK activity decreased the production levels of Aβ. On the contrary, if APP cells were incubated in medium containing no glucose (i.e., AMPK was activated), inhibition of AMPK activity largely increased Aβ production. As AMPK activation is a common defect in metabolic abnormalities, our study supports the premise that metabolic disorders may aggravate AD pathogenesis. PMID:26071020

  12. The natural products beauveriolide I and III: a new class of beta-amyloid-lowering compounds.

    PubMed

    Witter, Daniel P; Chen, Yanping; Rogel, Joseph K; Boldt, Grant E; Wentworth, Paul

    2009-05-25

    Attacking Alzheimer's by ACAT: The aggregation of beta-amyloid peptides, especially Abeta(42), into senile plaques is a hallmark of Alzheimer's disease (AD). We show that the fungal natural products beauveriolides I and III can potently decrease Abeta secretion from cells expressing human amyloid precursor protein; this offers a potential new scaffold for the development of compounds with proven bioavailability for the treatment of AD. PMID:19396893

  13. Cerebral autoregulation with changes in arterial and cerebral venous pressure

    SciTech Connect

    McPherson, R.W.; Traystman, R.J.

    1986-03-01

    The effect of cerebral venous pressure (Pcv) elevation on cerebral autoregulation has been incompletely studied. The authors compared the effect of decreased cerebral perfusion pressure (CPP) by elevated Pcv and decreased arterial pressure (Pa) on cerebral blood flow (CBF) in a canine modified bypass model. CPP of 80, 70, 60, 50, 40 and 30 mmHg were produced by decreasing Pa with intracranial pressure (ICP) and Pcv maintained at 0 mmHg (group 1, n = 5), or by elevating Pcv as Pa was maintained at 80 mmHg (group 2, n = 5. CBF was measured using radiolabeled microspheres, and CMRO/sub 2/ = CBF times arterial-sagittal sinus O/sub 2/ content difference. Cerebrovascular resistance (CVR) = CPP/CBF. In group 1 CBF (ml/100 gm/min) was unchanged from control (36 +/- 4) as CPP was decreased from 80 to 40 mmHg. As CPP was decreased to 30 mmHg, CBF decreased to 28 +/- 1. CVR (mmHg/ml/min/100 gm) was 2.3 +/- 0.3 and progressively decreased to 1.0 +/- 0.1 at CPP of 30 mmHg. In group 2 CBF was 34 +/- 3 and was unchanged as CPP decreased to 50 mmHg. At CPP of 40 and 30 mmHg CBF decreased to 25 +/- 3 and 22 +/- 2 respectively. Control CRV was 2.4 +/- 0.2 and progressively decreased to 1.4 +/- 0.1 as CPP decreased to 30 mmHg. CMRO/sub 2/ was unchanged from control in both groups. Thus, CBF is maintained to low CPP regardless of whether vascular transmural pressure was decreased (decrease Pa) or increased (increased Pcv) demonstrating that the myogenic mechanism of autoregulation may be unimportant in normoxic dogs.

  14. Nanomechanical properties of single amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  15. Microbial Manipulation of the Amyloid Fold

    PubMed Central

    DePas, William H.

    2012-01-01

    Microbial biofilms are encased in a protein, DNA and polysaccharide matrix that protects the community, promotes interactions with the environment, and helps cells to adhere together. The protein component of these matrices is often a remarkably stable, β-sheet-rich polymer called amyloid. Amyloids form ordered, self-templating fibers that are highly aggregative, making them a valuable biofilm component. Some eukaryotic proteins inappropriately adopt the amyloid fold and these misfolded protein aggregates disrupt normal cellular proteostasis, which can cause significant cytotoxicity. Indeed, until recently amyloids were considered solely the result of protein misfolding. However, research over the past decade has revealed how various organisms have capitalized on the amyloid fold by developing sophisticated biogenesis pathways that coordinate gene expression, protein folding, and secretion so that amyloid-related toxicities are minimized. How microbes manipulate amyloids, by augmenting their advantageous properties and by reducing their undesirable properties, will be the subject of this review. PMID:23108148

  16. Automated detection of β-amyloid-related cortical and subcortical signal changes in a transgenic model of Alzheimer’s disease using high-field MRI

    PubMed Central

    Teipel, Stefan J.; Kaza, Evangelia; Hadlich, Stefan; Bauer, Alexandra; Brüning, Thomas; Plath, Anne-Sophie; Krohn, Markus; Scheffler, Katja; Walker, Lary C.; Lotze, Martin; Pahnke, Jens

    2010-01-01

    In vivo imaging of β-amyloid load as a biomarker of Alzheimer’s disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten APP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. APP/PS1 mice present with rapid-onset cerebral β-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aβ-deposition in brain. Data were analyzed with a novel automated voxel-based analysis that allowed mapping the entire brain for significant signal changes. In APP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aβ plaques and activated microglia. Grey matter density did not differ between wild-type mice and APP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies. PMID:20966552

  17. Hydrostatic determinants of cerebral perfusion

    SciTech Connect

    Wagner, E.M.; Traystman, R.J.

    1986-05-01

    We examined the cerebral blood flow response to alterations in perfusion pressure mediated through decreases in mean arterial pressure, increases in cerebrospinal fluid (CSF) pressure, and increases in jugular venous (JV) pressure in 42 pentobarbital anesthetized dogs. Each of these three pressures was independently controlled. Cerebral perfusion pressure was defined as mean arterial pressure minus JV or CSF pressure, depending on which was greater. Mean hemispheric blood flow was measured with the radiolabeled microsphere technique. Despite 30-mm Hg reductions in mean arterial pressure or increases in CSF or JV pressure, CBF did not change as long as the perfusion pressure remained greater than approximately 60 mm Hg. However, whenever perfusion pressure was reduced to an average of 48 mm Hg, cerebral blood flow decreased 27% to 33%. These results demonstrate the capacity of the cerebral vascular bed to respond similarly to changes in the perfusion pressure gradient obtained by decreasing mean arterial pressure, increasing JV pressure or increasing CSF pressure, and thereby support the above definition of cerebral perfusion pressure.

  18. Employees with Cerebral Palsy

    MedlinePlus

    ... Resources Home | Accommodation and Compliance Series: Employees with Cerebral Palsy (CP) By Eddie Whidden, MA Preface Introduction Information About ... SOAR) at http://AskJAN.org/soar. Information about Cerebral Palsy (CP) What is CP? Cerebral palsy is a ...

  19. Cerebral Aneurysms Fact Sheet

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS Cerebral Aneurysms Fact Sheet See a list of all NINDS ... I get more information? What is a cerebral aneurysm? A cerebral aneurysm (also known as an intracranial ...

  20. Functional Changes in the Language Network in Response to Increased Amyloid β Deposition in Cognitively Intact Older Adults.

    PubMed

    Adamczuk, Katarzyna; De Weer, An-Sofie; Nelissen, Natalie; Dupont, Patrick; Sunaert, Stefan; Bettens, Karolien; Sleegers, Kristel; Van Broeckhoven, Christine; Van Laere, Koen; Vandenberghe, Rik

    2016-01-01

    Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden. PMID:25452579

  1. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease

    SciTech Connect

    van Duinen, S.G.; Castano, E.M.; Prelli, F.; Bots, G.T.A.B.; Luyendijk, W.; Frangione, B.

    1987-08-01

    Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related ..beta..-protein. Silver stain-positive, senile plaque-like structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approx. 4000 and its partial amino acid sequence to position 21 showed homology to the ..beta..-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of ..beta..-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

  2. Amyloid formation: functional friend or fearful foe?

    PubMed

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  3. Protective Role of S-Nitrosoglutathione (GSNO) Against Cognitive Impairment in Rat Model of Chronic Cerebral Hypoperfusion

    PubMed Central

    Won, Je-Seong; Kim, Jinsu; Annamalai, Balasubramaniam; Shunmugavel, Anandakumar; Singh, Inderjit; Singh, Avtar K.

    2014-01-01

    Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of Aβ and vascular inflammatory markers. GSNO treatment (50 μg/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the Aβ levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NFκB and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial Aβ uptake. Additionally, GSNO treatment inhibited the β-secretase activity in primary rat neuron cell culture, thus reducing secretion of Aβ, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease. PMID:23254638

  4. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

    PubMed Central

    Leuzy, Antoine; Chiotis, Konstantinos; Hasselbalch, Steen G.; Rinne, Juha O.; de Mendonça, Alexandre; Otto, Markus; Lleó, Alberto; Castelo-Branco, Miguel; Santana, Isabel; Johansson, Jarkko; Anderl-Straub, Sarah; von Arnim, Christine A. F.; Beer, Ambros; Blesa, Rafael; Fortea, Juan; Herukka, Sanna-Kaisa; Portelius, Erik; Pannee, Josef; Zetterberg, Henrik; Blennow, Kaj

    2016-01-01

    The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40. Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer’s and Parkinson’s Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer’s disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer’s disease, while more variable results were observed for cognitively normal and non-Alzheimer’s disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry

  5. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study.

    PubMed

    Leuzy, Antoine; Chiotis, Konstantinos; Hasselbalch, Steen G; Rinne, Juha O; de Mendonça, Alexandre; Otto, Markus; Lleó, Alberto; Castelo-Branco, Miguel; Santana, Isabel; Johansson, Jarkko; Anderl-Straub, Sarah; von Arnim, Christine A F; Beer, Ambros; Blesa, Rafael; Fortea, Juan; Herukka, Sanna-Kaisa; Portelius, Erik; Pannee, Josef; Zetterberg, Henrik; Blennow, Kaj; Nordberg, Agneta

    2016-09-01

    The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β42; (ii) centrally measured cerebrospinal fluid amyloid-β42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β42 to amyloid-β40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β42 and amyloid-β40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference

  6. Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP.

    PubMed Central

    Ghetti, B; Piccardo, P; Spillantini, M G; Ichimiya, Y; Porro, M; Perini, F; Kitamoto, T; Tateishi, J; Seiler, C; Frangione, B; Bugiani, O; Giaccone, G; Prelli, F; Goedert, M; Dlouhy, S R; Tagliavini, F

    1996-01-01

    Deposition of PrP amyloid in cerebral vessels in conjunction with neurofibrillary lesions is the neuropathologic hallmark of the dementia associated with a stop mutation at codon 145 of PRNP, the gene encoding the prion protein (PrP). In this disorder, the vascular amyloid in tissue sections and the approximately 7.5-kDa fragment extracted from amyloid are labeled by antibodies to epitopes located in the PrP sequence including amino acids 90-147. Amyloid-laden vessels are also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele is involved in the pathologic process. Abundant neurofibrillary lesions are present in the cerebral gray matter. They are composed of paired helical filaments, are labeled with antibodies that recognize multiple phosphorylation sites in tau protein, and are similar to those observed in Alzheimer disease. A PrP cerebral amyloid angiopathy has not been reported in diseases caused by PRNP mutations or in human transmissible spongiform encephalopathies; we propose to name this phenotype PrP cerebral amyloid angiopathy (PrP-CAA). Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:8570627

  7. Are elevated serum amyloid A levels and amyloid-enhancing factor sufficient to induce inflammation-associated amyloid deposition?

    PubMed

    Kisilevsky, R; Tan, R; Subrahmanyan, L; Snow, A

    1984-01-01

    During inflammation-associated amyloidosis two coincident factors, serum amyloid A (SAA) and amyloid-enhancing factor (AEF) are apparently necessary for amyloid A (AA) deposition. It is shown by passive transfer of cytokines, which stimulate SAA production, and AEF that these are not sufficient. A further factor(s) is necessary, which stems from the acute inflammatory response. Potential candidates are serum or tissue glycosaminoglycans. PMID:6400464

  8. Cerebral oxygenation and hyperthermia

    PubMed Central

    Bain, Anthony R.; Morrison, Shawnda A.; Ainslie, Philip N.

    2014-01-01

    Hyperthermia is associated with marked reductions in cerebral blood flow (CBF). Increased distribution of cardiac output to the periphery, increases in alveolar ventilation and resultant hypocapnia each contribute to the fall in CBF during passive hyperthermia; however, their relative contribution remains a point of contention, and probably depends on the experimental condition (e.g., posture and degree of hyperthermia). The hyperthermia-induced hyperventilatory response reduces arterial CO2 pressure (PaCO2) causing cerebral vasoconstriction and subsequent reductions in flow. During supine passive hyperthermia, the majority of recent data indicate that reductions in PaCO2 may be the primary, if not sole, culprit for reduced CBF. On the other hand, during more dynamic conditions (e.g., hemorrhage or orthostatic challenges), an inability to appropriately decrease peripheral vascular conductance presents a condition whereby adequate cerebral perfusion pressure may be compromised secondary to reductions in systemic blood pressure. Although studies have reported maintenance of pre-frontal cortex oxygenation (assessed by near-infrared spectroscopy) during exercise and severe heat stress, the influence of cutaneous blood flow is known to contaminate this measure. This review discusses the governing mechanisms associated with changes in CBF and oxygenation during moderate to severe (i.e., 1.0°C to 2.0°C increase in body core temperature) levels of hyperthermia. Future research directions are provided. PMID:24624095

  9. Amyloid Fibrils: Formation, Polymorphism, and Inhibition.

    PubMed

    Härd, Torleif

    2014-02-01

    Amyloid fibrils with cross-β spine basic architectures are prevalent and stable forms of peptides and proteins. Recent research has provided significant contributions to our understanding of the mechanisms of fibril formation and to the surprising diversity and persistence of structural polymorphism in amyloid fibrils. There have also been successful demonstrations of how molecules can be engineered to inhibit unwanted amyloid formation by different mechanisms. Future research in these areas will include investigations of mechanisms for primary nucleation and the structure of oligomeric intermediates, the general role of secondary nucleation events (autocatalysis), elucidation of the mechanisms and implications of preservation of structural morphology in amyloid propagation, and research into the largely unexplored phenomenon of cross-seeding, by which amyloid fibrils of one species induce the formation of amyloid by another species. PMID:26276617

  10. Insight into Amyloid Structure Using Chemical Probes

    PubMed Central

    Reinke, Ashley A.; Gestwicki, Jason E.

    2011-01-01

    Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by the deposition of amyloids in the brain. One prominent form of amyloid is composed of repeating units of the amyloid-β (Aβ) peptide. Over the past decade, it has become clear that these Aβ amyloids are not homogeneous; rather, they are composed of a series of structures varying in their overall size and shape and the number of Aβ peptides they contain. Recent theories suggest that these different amyloid conformations may play distinct roles in disease, although their relative contributions are still being discovered. Here, we review how chemical probes, such as congo red, thioflavin T and their derivatives, have been powerful tools for better understanding amyloid structure and function. Moreover, we discuss how design and deployment of conformationally selective probes might be used to test emerging models of AD. PMID:21457473

  11. Amyloid Goiter Secondary to Ulcerative Colitis

    PubMed Central

    Aydin, Bunyamin; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  12. Amyloid Structures as Biofilm Matrix Scaffolds.

    PubMed

    Taglialegna, Agustina; Lasa, Iñigo; Valle, Jaione

    2016-10-01

    Recent insights into bacterial biofilm matrix structures have induced a paradigm shift toward the recognition of amyloid fibers as common building block structures that confer stability to the exopolysaccharide matrix. Here we describe the functional amyloid systems related to biofilm matrix formation in both Gram-negative and Gram-positive bacteria and recent knowledge regarding the interaction of amyloids with other biofilm matrix components such as extracellular DNA (eDNA) and the host immune system. In addition, we summarize the efforts to identify compounds that target amyloid fibers for therapeutic purposes and recent developments that take advantage of the amyloid structure to engineer amyloid fibers of bacterial biofilm matrices for biotechnological applications. PMID:27185827

  13. Amyloid Goiter Secondary to Ulcerative Colitis.

    PubMed

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  14. Is Vasomotion in Cerebral Arteries Impaired in Alzheimer's Disease?

    PubMed

    Di Marco, Luigi Yuri; Farkas, Eszter; Martin, Chris; Venneri, Annalena; Frangi, Alejandro F

    2015-01-01

    A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer's disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion- the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain- is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Aβ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Aβ clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Aβ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Aβ and oxidative stress accumulation. PMID:25720414

  15. Early cortical thickness changes predict β-amyloid deposition in a mouse model of Alzheimer's disease.

    PubMed

    Grand'maison, Marilyn; Zehntner, Simone P; Ho, Ming-Kai; Hébert, François; Wood, Andrew; Carbonell, Felix; Zijdenbos, Alex P; Hamel, Edith; Bedell, Barry J

    2013-06-01

    Magnetic resonance imaging (MRI) studies have identified aberrant cortical structure in Alzheimer's disease (AD). The association between MRI-derived cortical morphometry measures and β-amyloid, however, remains poorly understood. In this study, we explored the potential relationship between early alterations in cortical thickness and later stage β-amyloid deposition, using a novel approach, in a transgenic AD mouse model. We acquired longitudinal anatomical MRI scans from mutant amyloid precursor protein (APP) transgenic mice and age-matched wild-type mice at 1 and 3.5months-of-age, and employed fully-automated image processing methods to derive objective, quantitative measures of cortical thickness on a region-of-interest basis. We also generated 3D quantitative immunohistochemistry (qIHC) volumes of deposited β-amyloid burden from 18month-old transgenic mice using an automated, production-level process. These studies revealed thinner cortex in most regions in the 1month-old transgenic mice relative to age-matched wild-types, with the exception of the frontal, perirhinal/entorhinal, posterior cingulate, and retrosplenial cortical regions. Between 1 and 3.5months-of-age, the transgenic mice demonstrated stable or increasing cortical thickness, while the wild-type mice showed cortical thinning. Based on data from co-registered 3D MRI and qIHC volumes, we identified an association between abnormal, early, regional cortical thickness change over 2.5months and later β-amyloid deposition. These observations suggest that the spatio-temporal pattern of early (pre-plaque) alterations in cerebral cortical structure is indicative of regional predisposition to later β-amyloid pathology in a transgenic AD mouse model. PMID:23454197

  16. Multimodal nanoprobes to target cerebrovascular amyloid in Alzheimer's disease brain.

    PubMed

    Jaruszewski, Kristen M; Curran, Geoffry L; Swaminathan, Suresh K; Rosenberg, Jens T; Grant, Samuel C; Ramakrishnan, Subramanian; Lowe, Val J; Poduslo, Joseph F; Kandimalla, Karunya K

    2014-02-01

    Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. CAA affects a majority of Alzheimer's disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid (CVA) and serving as early diagnostic and therapeutic agents. These nanovehicles were loaded with Gadolinium (Gd) based (Magnevist(®)) magnetic resonance imaging contrast agents or single photon emission computed tomography (SPECT) agents, such as (125)I. In addition, the nanovehicles carry either anti-inflammatory and anti-amyloidogenic agents such as curcumin or immunosuppressants such as dexamethasone, which were previously shown to reduce cerebrovascular inflammation. Owing to the anti-amyloid antibody (IgG4.1) grafted on the surface, the nanovehicles are capable of specifically targeting CVA deposits. The nanovehicles effectively marginate from the blood flow to the vascular wall as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. They demonstrate excellent distribution to the brain vasculature and target CVA, thus providing MRI and SPECT contrast specific to the CVA in the brain. In addition, they also display the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients. PMID:24331706

  17. The Human Disease-Associated Aβ Amyloid Core Sequence Forms Functional Amyloids in a Fungal Adhesin

    PubMed Central

    Rameau, Rachele D.; Jackson, Desmond N.; Beaussart, Audrey; Dufrêne, Yves F.

    2016-01-01

    ABSTRACT There is increasing evidence that many amyloids in living cells have physiological functions. On the surfaces of fungal cells, amyloid core sequences in adhesins can aggregate into 100- to 1,000-nm-wide patches to form high-avidity adhesion nanodomains on the cell surface. The nanodomains form through interactions that have amyloid-like properties: binding of amyloid dyes, perturbation by antiamyloid agents, and interaction with homologous sequences. To test whether these functional interactions are mediated by typical amyloid interactions, we substituted an amyloid core sequence, LVFFA, from human Aβ protein for the native sequence IVIVA in the 1,419-residue Candida albicans adhesin Als5p. The chimeric protein formed cell surface nanodomains and mediated cellular aggregation. The native sequence and chimeric adhesins responded similarly to the amyloid dye thioflavin T and to amyloid perturbants. However, unlike the native protein, the nanodomains formed by the chimeric protein were not force activated and formed less-robust aggregates under flow. These results showed the similarity of amyloid interactions in the amyloid core sequences of native Als5p and Aβ, but they also highlighted emergent properties of the native sequence. Also, a peptide composed of the Aβ amyloid sequence flanked by amino acids from the adhesin formed two-dimensional sheets with sizes similar to the cell surface patches of the adhesins. These results inform an initial model for the structure of fungal cell surface amyloid nanodomains. PMID:26758179

  18. Towards a Pharmacophore for Amyloid

    PubMed Central

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  19. [Amyloid deposition in chronic joint disease].

    PubMed

    Saitou, H

    1994-07-01

    As a screening procedure for the detection of amyloidosis secondary to rheumatoid arthritis, abdominal subcutaneous fat tissues were aspirated, and were examined after Congo red staining by polarized microscopy. Positive amyloid deposits were found in 7.1 percent of the rheumatoid patients, and the amyloid in the subcutaneous fat was determined to be AA type by permanganate oxidation. The occurrence of amyloid deposition was significantly correlated with the duration of the articular symptoms, the progression of the class, and also with proteinuria. Additionally the joint capsules, including the synovium and synovial fluid sediment, from patients with rheumatoid arthritis and osteoarthritis were examined for amyloid deposition. Deposits of amyloid in the hip and knee joints were found more frequently in those with rheumatoid arthritis than in those with osteoarthritis. In osteoarthritis, the frequency of amyloid deposition tended to increase with advancing age. However these amyloid deposits in the joint structure were discovered to be resistant to permanganate oxidation. Therefore it was suspected that these amyloid deposits were of a type different from AA amyloid. PMID:8071579

  20. Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis

    PubMed Central

    Annunziata, Ida; Patterson, Annette; Helton, Danielle; Hu, Huimin; Moshiach, Simon; Gomero, Elida; Nixon, Ralph; d’Azzo, Alessandra

    2013-01-01

    Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function – accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ-peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD. PMID:24225533

  1. Progressive intracranial hypertension and cerebral hypoperfusion in a fatal case of cerebral aspergilloma

    PubMed Central

    Toksvang, Linea Natalie; Plovsing, Ronni R; Berg, Ronan M G

    2014-01-01

    Summary We report a case of cerebral aspergilloma in a 25-year-old immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound. The present case illustrates that severe intracranial hypertension may evolve despite a normal opening pressure; it furthermore shows that continuous monitoring of intracranial pressure may be used to predict changes in cerebral haemodynamics in critically ill patients with neuroinfection. PMID:24907204

  2. Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.

    PubMed

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  3. Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid

    PubMed Central

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  4. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity.

    PubMed Central

    Takashima, A; Noguchi, K; Sato, K; Hoshino, T; Imahori, K

    1993-01-01

    Pathological changes of Alzheimer disease are characterized by cerebral cortical atrophy as a result of degeneration and loss of neurons. Typical histological lesions include numerous senile plaques composed of deposits of amyloid beta-protein and neurofibrillary tangles consisting predominantly of ubiquitin and highly phosphorylated tau proteins. Previously, tau protein kinase I (TPK I) was purified and its cDNA was cloned. To examine the biological role of this enzyme in neurons, we have studied the induction of its kinase activity in primary cultures of embryonic rat hippocampal neurons. Treatment of cultures with amyloid beta-protein significantly increased TPK I activity and induced the appearance of tau proteins recognized by the Alz-50 monoclonal antibody. In addition, though amyloid beta-protein was neurotoxic, either cycloheximide or actinomycin D prevented neuronal death. Death was also prevented by TPK I antisense oligonucleotides but not by sense oligonucleotides. These observations suggest that rat hippocampal neurons undergo programmed cell death in response to amyloid beta-protein and that TPK I is a key enzyme in this process. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:8356085

  5. Histological Staining of Amyloid and Pre-Amyloid Peptides and Proteins in Mouse Tissue

    PubMed Central

    Rajamohamedsait, Hameetha B.; Sigurdsson, Einar M.

    2013-01-01

    The increased availability of transgenic mouse models for studying human diseases has shifted the focus of many laboratories from in vitro to in vivo assays. Herein, methods are described to allow investigators to obtain well preserved mouse tissue to be stained with the standard histological dyes for amyloid, Congo Red and Thioflavin S. These sections can as well be used for immunohistological procedures that allow detection of tissue amyloid and pre-amyloid, such as those composed of the amyloid-β peptide, the tau protein, and the islet amyloid polypeptide. PMID:22528106

  6. [Plasma osmolarity and cerebral volume].

    PubMed

    Boulard, G

    2001-02-01

    Under normal physiological conditions, the osmolarity of extracellular fluids (ECFs) and natremia are controlled by two regulatory mechanisms modulating the water balance and sodium outflow from information collected by the osmoreceptors and baroreceptors, respectively. As well, under normal physiological conditions, water and electrolytes of brain ECFs are secreted by the endothelial cells of brain capillaries. Furthermore, isotonicity is present on both sides of the blood-brain barrier. In the event of systemic osmolarity disorders, water transport subject to osmosis laws occurs at the level of the blood-brain barrier. In the case of plasmatic hyperosmolarity cerebral dehydration is observed, while cerebral edema occurs in the contrary case. However, plasmatic osmolarity disorders have less effect on the cerebral volume when their introduction is slow. Experimentation in acute conditions shows that measured variations of the cerebral water content are lower than calculated variations, thus suggesting the existence of an adaptive mechanism, that is, the cerebral osmoregulation which limits the variation of the volume of brain cells by modulating their osmoactive molecule content. These osmoactive molecules are, on the one hand, the electrolytes, which are early and rapidly mobilized, and, on the other hand, the organic osmoles (amino acids, etc.), whose secretion is slower and delayed. This phenomenon should be taken into account in the treatment of osmolarity disorders. Thus, the related-risk of treatment for natremia disorders is therapeutic reversal of the osmotic gradient at the level of the blood-brain barrier. This reversal, which corresponds to a second osmotic stress, requires the implementation of a new procedure of cerebral osmoregulation in the opposite direction of the preceding one. As successive osmotic stresses decrease the effectiveness of brain osmoregulation, the risk for cerebral dehydration and pontine myelinolysis increases when the treatment

  7. [Cerebral palsy].

    PubMed

    Malagón Valdez, Jorge

    2007-01-01

    The term cerebral palsy (CP), is used for a great number of clinical neurological syndromes. The syndromes are characterized by having a common cause, motor defects. It is important, because they can cause a brain damage by presenting motor defects and some associated deficiencies, such as mental deficiency, epilepsy, language and visual defects and pseudobulbar paralysis, with the non-evolving fact. Some authors prefer using terms such as "non-evolving encephalopathies". In the treatment the utility of prevention programs of early stimulation and special rehabilitation methods, and treatment of associated deficiencies such as epilepsy, mental deficiency, language, audition and visual problems, and the attention deficit improve the prognosis in an important way. The prognosis depends on the severity of the disease and the associated manifestations. PMID:18422084

  8. Clinicians' ability to diagnose dementia with Lewy bodies is not affected by β-amyloid load

    PubMed Central

    Attems, Johannes; Thomas, Alan; Brown, Andrew; Jaros, Evelyn; Lett, Debbie J.; Ossola, Maria; Perry, Robert H.; Ramsay, Lynne; Walker, Lauren; McKeith, Ian G.

    2015-01-01

    Objective: To investigate whether an increasing load of β-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). Methods: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer β-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using α-synuclein immunostaining for Lewy body identification. β-Amyloid immunostaining was used for quantifying β-amyloid deposits. The Consortium to Establish a Registry for Alzheimer's Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. Results: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of β-amyloid plaque deposits. Conclusions: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while β-amyloid load has no effect. PMID:25552579

  9. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    PubMed Central

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-01-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. Images Fig. 2 Fig. 3 PMID:3924450

  10. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    PubMed

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-04-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. PMID:3924450

  11. Electroacupuncture attenuates cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive rats

    PubMed Central

    TAN, FENG; CHEN, JIE; LIANG, YANGUI; GU, MINHUA; LI, YANPING; WANG, XUEWEN; MENG, DI

    2014-01-01

    Cerebral ischemia induces injury, not only in the ischemic core and surrounding penumbra tissues, but also in remote areas such as the cervical spinal cord. The aim of the present study was to determine the effects of electroacupuncture (EA) on cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive (RHRSP) rats. The results demonstrated that neuronal loss, which was assayed by Nissl staining in the cervical spinal cords of RHRSP rats subjected to transient middle cerebral artery occlusion (MCAO), was markedly decreased by EA stimulation at the GV20 (Baihui) and GV14 (Dazhui) acupoints compared with that in rats undergoing sham stimulation. Quantitative polymerase chain reaction and western blot analysis demonstrated that EA stimulation blocked the MCAO-induced elevated protein expression levels of glial fibrillary acidic protein and amyloid precursor protein in the cervical spinal cord at days 24 and 48. To further investigate the mechanism underlying the neuroprotective role of EA stimulation, the protein expression levels of Nogo-A and Nogo-66 receptor-1 (NgR1), two key regulatory molecules for neurite growth, were recorded in each group. The results revealed that EA stimulation reduced the MCAO-induced elevation of Nogo-A and NgR1 protein levels at day 14 and 28 in RHRSP rats. Therefore, the results demonstrated that EA reduced cervical spinal cord injury following cerebral ischemia in RHRSP rats, indicating that EA has the potential to be developed as a therapeutic treatment agent for cervical spinal cord injury following stroke. PMID:24926338

  12. Effect of trichostatin A on gelsolin levels, proteolysis of amyloid precursor protein, and amyloid beta-protein load in the brain of transgenic mouse model of Alzheimer's disease.

    PubMed

    Yang, Wenzhong; Chauhan, Abha; Wegiel, Jerzy; Kuchna, Izabela; Gu, Feng; Chauhan, Ved

    2014-01-01

    In vivo and in vitro studies have shown that gelsolin is an anti-amyloidogenic protein. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the expression of gelsolin. Fibrillized amyoid beta-protein (Aβ) is a key constituent of amyloid plaques in the brains of patients with Alzheimer's disease (AD). We studied the effects of TSA on the levels of gelsolin; amyloid precursor protein (APP); proteolytic enzymes (γ-secretase and β-secretase) responsible for the production of Aβ; Aβ-cleaving enzymes, i.e., neprilysin (NEP) and insulin-degrading enzyme (IDE); and amyloid load in the double transgenic (Tg) APPswe/PS1(δE9) mouse model of AD. Intraperitoneal injection of TSA for two months (9-11 months of age) resulted in decreased activity of HDAC, and increased levels of gelsolin in the hippocampus and cortex of the brain in AD Tg mice as compared to vehicle-treated mice. TSA also increased the levels of γ-secretase and β-secretase activity in the brain. However, TSA did not show any effect on the activities or the expression levels of NEP and IDE in the brain. Furthermore, TSA treatment of AD Tg mice showed no change in the amyloid load (percent of examined area occupied by amyloid plaques) in the hippocampus and cortex, suggesting that TSA treatment did not result in the reduction of amyloid load. Interestingly, TSA prevented the formation of new amyloid deposits but increased the size of existing plaques. TSA treatment did not cause any apoptosis in the brain. These results suggest that TSA increases gelsolin expression in the brain, but the pleiotropic effects of TSA negate the anti-amyloidogenic effect of gelsolin in AD Tg mice. PMID:25387339

  13. Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

    PubMed Central

    Wiste, Heather J.; Weigand, Stephen D.; Knopman, David S.; Lowe, Val; Vemuri, Prashanthi; Mielke, Michelle M.; Jones, David T.; Senjem, Matthew L.; Gunter, Jeffrey L.; Gregg, Brian E.; Pankratz, Vernon S.; Petersen, Ronald C.

    2013-01-01

    Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity. Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison. Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. Conclusions: The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist. PMID:24132377

  14. Blood flow distribution in cerebral arteries

    PubMed Central

    Zarrinkoob, Laleh; Ambarki, Khalid; Wåhlin, Anders; Birgander, Richard; Eklund, Anders; Malm, Jan

    2015-01-01

    High-resolution phase–contrast magnetic resonance imaging can now assess flow in proximal and distal cerebral arteries. The aim of this study was to describe how total cerebral blood flow (tCBF) is distributed into the vascular tree with regard to age, sex and anatomic variations. Forty-nine healthy young (mean 25 years) and 45 elderly (mean 71 years) individuals were included. Blood flow rate (BFR) in 21 intra- and extracerebral arteries was measured. Total cerebral blood flow was defined as BFR in the internal carotid plus vertebral arteries and mean cerebral perfusion as tCBF/brain volume. Carotid/vertebral distribution was 72%/28% and was not related to age, sex, or brain volume. Total cerebral blood flow (717±123 mL/min) was distributed to each side as follows: middle cerebral artery (MCA), 21% distal MCA, 6% anterior cerebral artery (ACA), 12%, distal ACA, 4% ophthalmic artery, 2% posterior cerebral artery (PCA), 8% and 20% to basilar artery. Deviating distributions were observed in subjects with ‘fetal' PCA. Blood flow rate in cerebral arteries decreased with increasing age (P<0.05) but not in extracerebral arteries. Mean cerebral perfusion was higher in women (women: 61±8; men: 55±6 mL/min/100 mL, P<0.001). The study describes a new method to outline the flow profile of the cerebral vascular tree, including reference values, and should be used for grading the collateral flow system. PMID:25564234

  15. Amyloid-β efflux from the CNS into the plasma

    PubMed Central

    Roberts, Kaleigh Filisa; Elbert, Donald L.; Kasten, Tom P.; Patterson, Bruce W.; Sigurdson, Wendy C.; Connors, Rose E.; Ovod, Vitaliy; Munsell, Ling Y.; Mawuenyega, Kwasi G.; Miller-Thomas, Michelle M.; Moran, Christopher J.; Cross, Dewitte T.; Derdeyn, Colin P.; Bateman, Randall J.

    2015-01-01

    Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans. PMID:25205593

  16. Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice.

    PubMed

    Park, Sun Ah; Chevallier, Nathalie; Tejwani, Karishma; Hung, Mary M; Maruyama, Hiroko; Golde, Todd E; Koo, Edward H

    2016-09-01

    Epidemiologic studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk for developing Alzheimer's disease (AD). Because the primary mode of action of NSAIDs is to inhibit cyclooxygenase (COX) activity, it has been proposed that perturbed activity of COX-1 or COX-2 contributes to AD pathogenesis. To test the role of COX-1 or COX-2 in amyloid deposition and amyloid-associated inflammatory changes, we examined amyloid precursor protein (APP) transgenic mice in the context of either COX-1 or COX-2 deficiency. Our studies showed that loss of either COX-1 or COX-2 gene did not alter amyloid burden in brains of the APP transgenic mice. However, one marker of microglial activation (CD45) was decreased in brains of COX-1 deficient/APP animals and showed a strong trend in reduction in COX-2 deficient/APP animals. These results suggest that COX activity and amyloid deposition in brain are likely independent processes. Further, if NSAIDs do causally reduce the risks of AD, then our findings indicate that the mechanisms are likely not due primarily to their inhibition on COX or γ-secretase modulation activity, the latter reported recently after acute dosing of ibuprofen in humans and nonhuman primates. PMID:27425247

  17. Yuzu extract prevents cognitive decline and impaired glucose homeostasis in β-amyloid-infused rats.

    PubMed

    Yang, Hye Jeong; Hwang, Jin Taek; Kwon, Dae Young; Kim, Min Jung; Kang, Suna; Moon, Na Rang; Park, Sunmin

    2013-07-01

    Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid-induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35-25) [non-plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40-120 min after glucose loading during an oral-glucose-tolerance test, but not at 0-40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion. PMID:23719224

  18. Chiral recognition in amyloid fiber growth.

    PubMed

    Torbeev, Vladimir; Grogg, Marcel; Ruiz, Jérémy; Boehringer, Régis; Schirer, Alicia; Hellwig, Petra; Jeschke, Gunnar; Hilvert, Donald

    2016-05-01

    Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41]-fragment of human β2-microglobulin (β2m) and the 99-residue full-length protein. For the dimeric [20-41]β2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length β2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-β2m amyloids. Furthermore, the full-length d-enantiomer of β2m was found to be an efficient inhibitor of l-β2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:26929241

  19. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  20. Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice.

    PubMed

    Thakker, Deepak R; Sankaranarayanan, Sethu; Weatherspoon, Marcy R; Harrison, Jonathan; Pierdomenico, Maria; Heisel, Jennifer M; Thompson, Lorin A; Haskell, Roy; Grace, James E; Taylor, Sarah J; Albright, Charles F; Shafer, Lisa L

    2015-04-29

    Multiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 μg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 μm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aβ levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 μg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD. PMID:25926467

  1. Reelin protects against amyloid β toxicity in vivo

    PubMed Central

    Lane-Donovan, Courtney; Philips, Gary T.; Wasser, Catherine R.; Durakoglugil, Murat S.; Masiulis, Irene; Upadhaya, Ajeet; Pohlkamp, Theresa; Coskun, Cagil; Kotti, Tiina; Steller, Laura; Hammer, Robert E.; Frotscher, Michael; Bock, Hans H.; Herz, Joachim

    2015-01-01

    Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and the most common form of dementia in people over the age of 65. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin, which is a physiological ligand for the multifunctional ApoE receptors Apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr), enhances synaptic plasticity. We have previously shown that the presence of ApoE4 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. Here, we show that when Reelin was knocked out in adult mice, these mice behaved normally without overt learning or memory deficits. However, they were strikingly sensitive to amyloid-induced synaptic suppression, and had profound memory and learning disabilities at very low amounts of amyloid deposition. Our findings highlight the physiological importance of Reelin in protecting the brain against Aβ-induced synaptic dysfunction and memory impairment. PMID:26152694

  2. Reelin protects against amyloid β toxicity in vivo.

    PubMed

    Lane-Donovan, Courtney; Philips, Gary T; Wasser, Catherine R; Durakoglugil, Murat S; Masiulis, Irene; Upadhaya, Ajeet; Pohlkamp, Theresa; Coskun, Cagil; Kotti, Tiina; Steller, Laura; Hammer, Robert E; Frotscher, Michael; Bock, Hans H; Herz, Joachim

    2015-07-01

    Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and is the most common form of dementia in people over the age of 65 years. The predominant genetic risk factor for AD is the ε4 allele encoding apolipoprotein E (ApoE4). The secreted glycoprotein Reelin enhances synaptic plasticity by binding to the multifunctional ApoE receptors apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr). We have previously shown that the presence of ApoE4 renders neurons unresponsive to Reelin by impairing the recycling of the receptors, thereby decreasing its protective effects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. We showed that when Reelin was knocked out in adult mice, these mice behaved normally without overt learning or memory deficits. However, they were strikingly sensitive to amyloid-induced synaptic suppression and had profound memory and learning disabilities with very low amounts of amyloid deposition. Our findings highlight the physiological importance of Reelin in protecting the brain against Aβ-induced synaptic dysfunction and memory impairment. PMID:26152694

  3. Nucleation of polymorphic amyloid fibrils.

    PubMed

    Auer, Stefan

    2015-03-10

    One and the same protein can self-assemble into amyloid fibrils with different morphologies. The phenomenon of fibril polymorphism is relevant biologically because different fibril polymorphs can have different toxicity, but there is no tool for predicting which polymorph forms and under what conditions. Here, we consider the nucleation of polymorphic amyloid fibrils occurring by direct polymerization of monomeric proteins into fibrils. We treat this process within the framework of our newly developed nonstandard nucleation theory, which allows prediction of the concentration dependence of the nucleation rate for different fibril polymorphs. The results highlight that the concentration dependence of the nucleation rate is closely linked with the protein solubility and a threshold monomer concentration below which fibril formation becomes biologically irrelevant. The relation between the nucleation rate, the fibril solubility, the threshold concentration, and the binding energies of the fibril building blocks within fibrils might prove a valuable tool for designing new experiments to control the formation of particular fibril polymorphs. PMID:25762329

  4. Alzheimer's Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome

    PubMed Central

    Lu, Suqian; Burton, Mark A.; Ghosh, Joy G.; Ericsson, Maria; Soscia, Stephanie J.; Mocofanescu, Anca; Folkerth, Rebecca D.; Robb, Richard M.; Kuszak, Jer R.; Clark, John I.; Tanzi, Rudolph E.; Hunter, David G.; Goldstein, Lee E.

    2010-01-01

    Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-β peptides (Aβ), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Aβ accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Aβ pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Aβ accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Aβ aggregates (∼5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Aβ in DS lenses. Incubation of synthetic Aβ with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Aβ accumulation as a key pathogenic

  5. Exercise engagement as a moderator of APOE effects on amyloid deposition

    PubMed Central

    Head, Denise; Bugg, Julie M.; Goate, Alison M.; Fagan, Anne M.; Mintun, Mark A.; Benzinger, Tammie; Holtzman, David M.; Morris, John C.

    2012-01-01

    Objective APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults. Method APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association. Subjects 201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants. Results APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments. Conclusion Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition. PMID:22232206

  6. [German Society of Nuclear Medicine procedure guideline on beta-amyloid brain PET imaging].

    PubMed

    Barthel, Henryk; Meyer, Philipp T; Drzezga, Alexander; Bartenstein, Peter; Boecker, Henning; Brust, Peter; Buchert, Ralph; Coenen, Heinz H; la Fougère, Christian; Gründer, Gerhard; Grünwald, Frank; Krause, Bernd J; Kuwert, Torsten; Schreckenberger, Matthias; Tatsch, Klaus; Langen, Karl-Josef; Sabri, Osama

    2016-08-01

    Recently, a number of positron emission tomography (PET) radiotracers have been approved for clinical use. These tracers target cerebral beta-amyloid (Aβ) plaques, a hallmark of Alzheimer's disease. Increasing use of this method implies the need for respective standards. This German Society of Nuclear Medicine guideline describes adequate procedures for Aβ plaque PET imaging. It not only discusses the tracers used for that purpose, but also lists measures for correct patient preparation, image data generation, processing, analysis and interpretation. With that, this "S1" category (according to the German Association of the Scientific Medical Societies standard) guideline aims at contributing to quality assurance of nuclear imaging in Germany. PMID:27080914

  7. Nanofluidic Biosensing for β-amyloid Detection Using Surface Enhanced Raman Spectroscopy (SERS)

    PubMed Central

    Chou, I-Hsien; Benford, Melodie; Beier, Hope T.; Coté, Gerard L.; Wang, Miao; Jing, Nan; Kameoka, Jun; Good, Theresa A.

    2008-01-01

    Trace detection of the conformational transition of β-amyloid peptide (Aβ) from a predominantly α-helical structure to β-sheet could have a large impact in understanding and diagnosing Alzheimer’s disease. We demonstrate how a novel nanofluidic biosensor using a controlled, reproducible surface enhanced Raman spectroscopy active site was developed to observe Aβ in different conformational states during the Aβ self-assembly process as well as to distinguish Aβ from confounder proteins commonly found in cerebral spinal fluid. PMID:18489171

  8. Amyloid-Associated Nucleic Acid Hybridisation

    PubMed Central

    Braun, Sebastian; Humphreys, Christine; Fraser, Elizabeth; Brancale, Andrea; Bochtler, Matthias; Dale, Trevor C.

    2011-01-01

    Nucleic acids promote amyloid formation in diseases including Alzheimer's and Creutzfeldt-Jakob disease. However, it remains unclear whether the close interactions between amyloid and nucleic acid allow nucleic acid secondary structure to play a role in modulating amyloid structure and function. Here we have used a simplified system of short basic peptides with alternating hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid interactions. Employing biophysical techniques including X-ray fibre diffraction, circular dichroism spectroscopy and electron microscopy we show that the polymerized charges of nucleic acids concentrate and enhance the formation of amyloid from short basic peptides, many of which would not otherwise form fibres. In turn, the amyloid component binds nucleic acids and promotes their hybridisation at concentrations below their solution Kd, as shown by time-resolved FRET studies. The self-reinforcing interactions between peptides and nucleic acids lead to the formation of amyloid nucleic acid (ANA) fibres whose properties are distinct from their component polymers. In addition to their importance in disease and potential in engineering, ANA fibres formed from prebiotically-produced peptides and nucleic acids may have played a role in early evolution, constituting the first entities subject to Darwinian evolution. PMID:21625537

  9. United Cerebral Palsy

    MedlinePlus

    ... of UCP blog for the latest updates. United Cerebral Palsy UCP educates, advocates and provides support services to ... Partners Merz Logo Sprint Relay Copyright © 2015 United Cerebral Palsy 1825 K Street NW Suite 600 Washington, DC ...

  10. Cerebral Contusions and Lacerations

    MedlinePlus

    ... Stretch Additional Content Medical News Cerebral Contusions and Lacerations By James E. Wilberger, MD, Derrick A. Dupre, ... a direct, strong blow to the head. Cerebral lacerations are tears in brain tissue, caused by a ...

  11. Patterns of human local cerebral glucose metabolism during epileptic seizures

    SciTech Connect

    Engel, J. Jr.; Kuhl, D.E.; Phelps, M.E.

    1982-10-01

    Ictal patterns of local cerebral metabolic rate have been studied in epileptic patients by positron computed tomography with /sup 18/F-labeled 2-fluoro-2-deoxy-D-glucose. Partial seizures were associated with activation of anatomic structures unique to each patient studied. Ictal increases and decreases in local cerebral metabolism were observed. Scans performed during generalized convulsions induced by electroshock demonstrated a diffuse ictal increase and postictal decrease in cerebral metabolism. Petit mal absences were associated with a diffuse increase in cerebral metabolic rate. The ictal fluorodeoxyglucose patterns obtained from patients do not resemble autoradiographic patterns obtained from common experimental animal models of epilepsy.

  12. Chronic cerebral hypoperfusion induces memory deficits and facilitates Aβ generation in C57BL/6J mice.

    PubMed

    Wang, Lingxi; Du, Yehong; Wang, Kejian; Xu, Ge; Luo, Shifang; He, Guiqiong

    2016-09-01

    Alzheimer's disease (AD) is the most common type of dementia frequently responsible for cognitive decline in the elderly. The etiology and molecular mechanism of AD pathogenesis remain inconclusive. Aging and vascular factors are important independent causes and contributors to sporadic AD. Clinical imaging studies showed that cerebral blood flow decreases before cognitive impairment in patients with AD. To investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive impairment and morphological features, we developed a new manner of CCH mouse model by narrowing bilateral common carotid arteries. Mice started to manifest spatial memory deficits 1month after the surgery and exhibited behavioral changes in a time-dependent manner. Mice also presented memory deficits accompanied with morphological changes at the neuronal and synaptic levels. CCH damaged the normal neuronal morphology and significantly reduced the expression level of PSD95. CCH activated astrocytes, increased the co-expression of GFAP and AQP4, and destroyed the blood-brain barrier (BBB). Furthermore, CCH facilitated intracellular and extracellular Aβ deposition by up-regulating γ-secretase and β-secretase levels. Our results showed good reproducibility of post-CCH pathological processes, which are characterized by neuronal apoptosis, axonal abnormalities, glial activation, BBB damage, amyloid deposition, and cognitive dysfunction; these processes may be used to decipher the complex interplay and pathological process between CCH and AD. This study provides laboratory evidence for the prevention and treatment of cognitive malfunction and AD. PMID:27421879

  13. All-atom Simulation of Amyloid Aggregates

    NASA Astrophysics Data System (ADS)

    Berhanu, Workalemahu M.; Alred, Erik J.; Bernhardt, Nathan A.; Hansmann, Ulrich H. E.

    Molecular simulations are now commonly used to complement experiments in the investigation of amyloid formation and their role in human diseases. While various simulations based on enhanced sampling techniques are used in amyloid formation simulations, this article will focus on those using standard atomistic simulations to evaluate the stability of fibril models. Such studies explore the limitations that arise from the choice of force field or polymorphism; and explore the stability of in vivo and in vitro forms of Aβ fibril aggregates, and the role of heterologous seeding as a link between different amyloid diseases.

  14. Cerebral Hypoperfusion Precedes Nausea During Centrifugation

    NASA Technical Reports Server (NTRS)

    Serrador, Jorge M.; Schlegel, Todd T.; Black, F. Owen; Wood, Scott J.

    2004-01-01

    Nausea and motion sickness are important operational concerns for aviators and astronauts. Understanding underlying mechanisms associated with motion sickness may lead to new treatments. The goal of this work was to determine if cerebral blood flow changes precede the development of nausea in motion sick susceptible subjects. Cerebral flow velocity in the middle cerebral artery (transcranial Doppler), blood pressure (Finapres) and end-tidal CO2 were measured while subjects were rotated on a centrifuge (250 degrees/sec). Following 5 min of rotation, subjects were translated 0.504 m off-center, creating a +lGx centripetal acceleration in the nasal-occipital plane. Ten subjects completed the protocol without symptoms while 5 developed nausea (4 while 6ff-center and 1 while rotating on-center). Prior to nausea, subjects had significant increases in blood pressure (+13plus or minus 3 mmHg, P less than 0.05) and cerebrovascular resistance (+46 plus or minus 17%, P less than 0.05) and decreases in cerebral flow velocity both in the second (-13 plus or minus 4%) and last minute (-22 plus or minus 5%) before symptoms (P less than 0.05). In comparison, controls demonstrated no change in blood pressure or cerebrovascular resistance in the last minute of off-center rotation and only a 7 plus or minus 2% decrease in cerebral flow velocity. All subjects had significant hypocapnia (-3.8 plus or minus 0.4 mmHg, P less than 0.05), however this hypocapnia could not fully explain the cerebral hypoperfusion associated with the development of nausea. These data indicate that reductions in cerebral blood flow precede the development of nausea. Further work is necessary to determine what role cerebral hypoperfusion plays in motion sickness and whether cerebral hypoperfusion can be used to predict the development of nausea in susceptible individuals.

  15. Cerebral Lactate Metabolism After Traumatic Brain Injury.

    PubMed

    Patet, Camille; Suys, Tamarah; Carteron, Laurent; Oddo, Mauro

    2016-04-01

    Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome. PMID:26898683

  16. Aging and Cerebral Palsy.

    ERIC Educational Resources Information Center

    Networker, 1993

    1993-01-01

    This special edition of "The Networker" contains several articles focusing on aging and cerebral palsy (CP). "Aging and Cerebral Palsy: Pathways to Successful Aging" (Jenny C. Overeynder) reports on the National Invitational Colloquium on Aging and Cerebral Palsy held in April 1993. "Observations from an Observer" (Kathleen K. Barrett) describes…

  17. Cerebral Microbleeds: A Review of Clinical, Genetic, and Neuroimaging Associations

    PubMed Central

    Yates, Paul A.; Villemagne, Victor L.; Ellis, Kathryn A.; Desmond, Patricia M.; Masters, Colin L.; Rowe, Christopher C.

    2013-01-01

    Cerebral microbleeds (microbleeds) are small, punctuate hypointense lesions seen in T2* Gradient-Recall Echo (GRE) and Susceptibility-Weighted (SWI) Magnetic Resonance Imaging (MRI) sequences, corresponding to areas of hemosiderin breakdown products from prior microscopic hemorrhages. They occur in the setting of impaired small vessel integrity, commonly due to either hypertensive vasculopathy or cerebral amyloid angiopathy. Microbleeds are more prevalent in individuals with Alzheimer’s disease (AD) dementia and in those with both ischemic and hemorrhagic stroke. However they are also found in asymptomatic individuals, with increasing prevalence with age, particularly in carriers of the Apolipoprotein (APOE) ε4 allele. Other neuroimaging findings that have been linked with microbleeds include lacunar infarcts and white matter hyperintensities on MRI, and increased cerebral β-amyloid burden using 11C-PiB Positron Emission Tomography. The presence of microbleeds has been suggested to confer increased risk of incident intracerebral hemorrhage – particularly in the setting of anticoagulation – and of complications of immunotherapy for AD. Prospective data regarding the natural history and sequelae of microbleeds are currently limited, however there is a growing evidence base that will serve to inform clinical decision-making in the future. PMID:24432010

  18. Effects of Huanglian-Jie-Du-Tang and its modified formula on the modulation of amyloid-β precursor protein processing in Alzheimer's disease models.

    PubMed

    Durairajan, Siva Sundara Kumar; Huang, Ying-Yu; Yuen, Pui-Yee; Chen, Lei-Lei; Kwok, Ka-Yan; Liu, Liang-Feng; Song, Ju-Xian; Han, Quan-Bin; Xue, Lei; Chung, Sookja K; Huang, Jian-Dong; Baum, Larry; Senapati, Sanjib; Li, Min

    2014-01-01

    Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-β precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPβ-Swedish and reduced the generation of Aβ peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aβ- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aβ production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aβ plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aβ. Further study of HLJDT-M for therapeutic use in treating AD is

  19. Effects of Huanglian-Jie-Du-Tang and Its Modified Formula on the Modulation of Amyloid-β Precursor Protein Processing in Alzheimer's Disease Models

    PubMed Central

    Durairajan, Siva Sundara Kumar; Huang, Ying-Yu; Yuen, Pui-Yee; Chen, Lei-Lei; Kwok, Ka-Yan; Liu, Liang-Feng; Song, Ju-Xian; Han, Quan-Bin; Xue, Lei; K. Chung, Sookja; Huang, Jian-Dong; Baum, Larry; Senapati, Sanjib; Li, Min

    2014-01-01

    Huanglian-Jie-Du-Tang (HLJDT) is a famous traditional Chinese herbal formula that has been widely used clinically to treat cerebral ischemia. Recently, we found that berberine, a major alkaloid compound in HLJDT, reduced amyloid-β (Aβ) accumulation in an Alzheimer’s disease (AD) mouse model. In this study, we compared the effects of HLJDT, four single component herbs of HLJDT (Rhizoma coptidis (RC), Radix scutellariae (RS), Cortex phellodendri (CP) and Fructus gardenia (FG)) and the modified formula of HLJDT (HLJDT-M, which is free of RS) on the regulatory processing of amyloid-β precursor protein (APP) in an in vitro model of AD. Here we show that treatment with HLJDT-M and its components RC, CP, and the main compound berberine on N2a mouse neuroblastoma cells stably expressing human APP with the Swedish mutation (N2a-SwedAPP) significantly decreased the levels of full-length APP, phosphorylated APP at threonine 668, C-terminal fragments of APP, soluble APP (sAPP)-α and sAPPβ-Swedish and reduced the generation of Aβ peptide in the cell lysates of N2a-SwedAPP. HLJDT-M showed more significant APP- and Aβ- reducing effects than berberine, RC or CP treatment alone. In contrast, HLJDT, its component RS and the main active compound of RS, baicalein, strongly increased the levels of all the metabolic products of APP in the cell lysates. The extract from FG, however, did not influence APP modulation. Interestingly, regular treatment of TgCRND8 APP transgenic mice with baicalein exacerbated the amyloid plaque burden, APP metabolism and Aβ production. Taken together, these data provide convincing evidence that HLJDT and baicalein treatment can increase the amyloidogenic metabolism of APP which is at least partly responsible for the baicalein-mediated Aβ plaque increase in the brains of TgCRND8 mice. On the other hand, HLJDT-M significantly decreased all the APP metabolic products including Aβ. Further study of HLJDT-M for therapeutic use in treating AD is

  20. The multiple mechanisms of amyloid deposition

    PubMed Central

    Mena, Maria A; Rodríguez-Navarro, José A

    2009-01-01

    Amyloid deposition is one of the central neuropathological abnormalities in Alzheimer disease (AD) but it also takes places in many neurodegenerative diseases such as prionic disorders, Huntington's disease (HD) and others. Up to very recently amyloid formation was considered a very slow process of deposition of an abnormal protein due to genetic abnormalities or post-translational modification of the deposited protein. Recent data suggest that the process of amyloidogenesis may be much more rapid in many cases and due to multiple mechanisms. We have found a mouse model of progressive neurodegeneration that resemble motor, behavioral and pathological hallmarks of parkinsonism and tauopathies, but surprisingly, also present amyloid deposits in brain and peripheral organs. Here we review some of these recent works which may provide new insight into the process of formation of amyloid and, perhaps, new ideas for its treatment. PMID:19270506

  1. Polymorphism of Amyloid Fibrils In Vivo.

    PubMed

    Annamalai, Karthikeyan; Gührs, Karl-Heinz; Koehler, Rolf; Schmidt, Matthias; Michel, Henri; Loos, Cornelia; Gaffney, Patricia M; Sigurdson, Christina J; Hegenbart, Ute; Schönland, Stefan; Fändrich, Marcus

    2016-04-01

    Polymorphism is a wide-spread feature of amyloid-like fibrils formed in vitro, but it has so far remained unclear whether the fibrils formed within a patient are also affected by this phenomenon. In this study we show that the amyloid fibrils within a diseased individual can vary considerably in their three-dimensional architecture. We demonstrate this heterogeneity with amyloid fibrils deposited within different organs, formed from sequentially non-homologous polypeptide chains and affecting human or animals. Irrespective of amyloid type or source, we found in vivo fibrils to be polymorphic. These data imply that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved in vivo and in vitro. PMID:26954430

  2. Amyloid Polymorphism: Structural Basis and Neurobiological Relevance

    PubMed Central

    Tycko, Robert

    2015-01-01

    Summary Our understanding of the molecular structures of amyloid fibrils that are associated with neurodegenerative diseases, of mechanisms by which disease-associated peptides and proteins aggregate into fibrils, and of structural properties of aggregation intermediates has advanced considerably in recent years. Detailed molecular structural models for certain fibrils and aggregation intermediates are now available. It is now well established that amyloid fibrils are generally polymorphic at the molecular level, with a given peptide or protein being capable of forming a variety of distinct, self-propagating fibril structures. Recent results from structural studies and from studies involving cell cultures, transgenic animals, and human tissue provide initial evidence that molecular structural variations in amyloid fibrils and related aggregates may correlate with or even produce variations in disease development. This article reviews our current knowledge of the structural and mechanistic aspects of amyloid formation, as well as current evidence for the biological relevance of structural variations. PMID:25950632

  3. Multiphoton absorption in amyloid protein fibres

    NASA Astrophysics Data System (ADS)

    Hanczyc, Piotr; Samoc, Marek; Norden, Bengt

    2013-12-01

    Fibrillization of peptides leads to the formation of amyloid fibres, which, when in large aggregates, are responsible for diseases such as Alzheimer's and Parkinson's. Here, we show that amyloids have strong nonlinear optical absorption, which is not present in native non-fibrillized protein. Z-scan and pump-probe experiments indicate that insulin and lysozyme β-amyloids, as well as α-synuclein fibres, exhibit either two-photon, three-photon or higher multiphoton absorption processes, depending on the wavelength of light. We propose that the enhanced multiphoton absorption is due to a cooperative mechanism involving through-space dipolar coupling between excited states of aromatic amino acids densely packed in the fibrous structures. This finding will provide the opportunity to develop nonlinear optical techniques to detect and study amyloid structures and also suggests that new protein-based materials with sizable multiphoton absorption could be designed for specific applications in nanotechnology, photonics and optoelectronics.

  4. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions.

    PubMed

    Zhang, Rui; Miao, Qian-Wei; Zhu, Chun-Xiao; Zhao, Yue; Liu, Li; Yang, Jun; An, Li

    2015-03-01

    Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly individuals and its effective therapies are still unavailable. This study was designed to investigate the neuroprotection of sulforaphane (SFN) in AD-lesion mice induced by combined administration of d-galactose and aluminium. Results showed that SFN ameliorated spatial cognitive impairment and locomotor activity decrease in Morris water maze and open field test, respectively. And attenuated numbers of amyloid β (Aβ) plaques in both hippocampus and cerebral cortex of AD-lesion mice were detected by immunohistochemistry. According to spectrophotometry and quantitative reverse-transcriptase polymerase chain reaction results, a significant increase in carbonyl group level and obvious decreases in both activity and messenger RNA expression of glutathione peroxidase were found in brain of AD-lesion mice compared with control, but not in SFN-treated AD-lesion mice. In conclusion, SFN ameliorates neurobehavioral deficits and protects the brain from Aβ deposits and peroxidation in mice with Alzheimer-like lesions, suggesting SFN is likely a potential phytochemical to be used in AD therapeutics. PMID:25024455

  5. Islet amyloid polypeptide and high hydrostatic pressure: towards an understanding of the fibrillization process

    NASA Astrophysics Data System (ADS)

    Lopes, D. H. J.; Smirnovas, V.; Winter, R.

    2008-07-01

    Type II Diabetes Mellitus is a disease which is characterized by peripheral insulin resistance coupled with a progressive loss of insulin secretion that is associated with a decrease in pancreatic islet β-cell mass and the deposition of amyloid in the extracellular matrix of β-cells, which lead to islet cell death. The principal component of the islet amyloid is a pancreatic hormone called islet amyloid polypeptide (IAPP). High-pressure coupled with FT-IR, CD, ThT fluorescence spectroscopic and AFM studies were carried out to reveal information on the aggregation pathway as well as the aggregate structure of IAPP. Our data indicate that IAPP pre-formed fibrils exhibit a strong polymorphism with heterogeneous structures very sensitive to high hydrostatic pressure, indicating a high percentage of ionic and hydrophobic interactions being responsible for the stability the IAPP fibrils.

  6. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology.

    PubMed

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  7. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    PubMed Central

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G.; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P.

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  8. Fibril Fragmentation Enhances Amyloid Cytotoxicity*♦

    PubMed Central

    Xue, Wei-Feng; Hellewell, Andrew L.; Gosal, Walraj S.; Homans, Steve W.; Hewitt, Eric W.; Radford, Sheena E.

    2009-01-01

    Fibrils associated with amyloid disease are molecular assemblies of key biological importance, yet how cells respond to the presence of amyloid remains unclear. Cellular responses may not only depend on the chemical composition or molecular properties of the amyloid fibrils, but their physical attributes such as length, width, or surface area may also play important roles. Here, we report a systematic investigation of the effect of fragmentation on the structural and biological properties of amyloid fibrils. In addition to the expected relationship between fragmentation and the ability to seed, we show a striking finding that fibril length correlates with the ability to disrupt membranes and to reduce cell viability. Thus, despite otherwise unchanged molecular architecture, shorter fibrillar samples show enhanced cytotoxic potential than their longer counterparts. The results highlight the importance of fibril length in amyloid disease, with fragmentation not only providing a mechanism by which fibril load can be rapidly increased but also creating fibrillar species of different dimensions that can endow new or enhanced biological properties such as amyloid cytotoxicity. PMID:19808677

  9. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    PubMed

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane. PMID:26673736

  10. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  11. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    NASA Astrophysics Data System (ADS)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  12. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s disease

    PubMed Central

    Canobbio, Ilaria; Abubaker, Aisha Alsheikh; Visconte, Caterina; Torti, Mauro; Pula, Giordano

    2015-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the “vascular hypothesis”, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease. PMID:25784858

  13. Preferential Transport Theory for Beta-Amyloid Clearance from the Brain

    NASA Astrophysics Data System (ADS)

    Coloma, Mikhail; Schaffer, David; Chiarot, Paul; Huang, Peter

    2015-11-01

    The failure to clear beta-amyloid from the aging brain leads to its accumulation within the walls of arteries and to Alzheimer's disease. However, the transport mechanism for beta-amyloid clearance is not well understood. In this study, we propose a preferential transport theory for flow within the vascular walls in the cerebral arterial basement membrane. The flow conduit within the arterial basement membrane is modeled as an annulus between deformable concentric cylinders filled with an incompressible, single-phase Newtonian fluid. The transport is driven by arterial lumen deformation induced by heart pulsations superimposed with reflected boundary waves. Our theory predicts that while the overall arterial wave propagation is in the same direction as the blood flow toward the capillaries, a reverse flow in the basement membrane can be preferentially induced toward larger arteries. This has been suggested as a potential clearance pathway for beta-amyloid. We estimate the magnitude of the reverse transport through a control volume analysis which is corroborated by numerical solutions of the Navier-Stokes equations. Bench-top experiments to validate our computational models are presented.

  14. Hypothermia reduces cerebral metabolic rate and cerebral blood flow in newborn pigs

    SciTech Connect

    Busija, D.W.; Leffler, C.W. )

    1987-10-01

    The authors examined effects of hypothermia on cerebral metabolic rate and cerebral blood flow in anesthetized, newborn pigs (1-4 days old). Cerebral blood flow (CBF) was determined with 15-{mu}m radioactive microspheres. Regional CBF ranged from 44 to 66 ml{center dot}min{sup {minus}1}{center dot}100 g{sup {minus}1}, and cerebral metabolic rate was 1.94 {plus minus} 0.23 ml O{sub 2}{center dot}100 g{sup {minus}1}{center dot}min{sup {minus}1} during normothermia (39{degree}C). Reduction of rectal temperature to 34-35{degree}C decreased CBF and cerebral metabolic rate 40-50%. In another group of piglets, they examined responsiveness of the cerebral circulation to arterial hypercapnia during hypothermia. Although absolute values for normocapnic and hypercapnic CBF were reduced by hypothermia and absolute values for normocapnic and hypercapnic cerebrovascular resistance were increased, the percentage changes from control in these variables during hypercapnia were similar during normothermia and hypothermia. In another group of animals that were maintained normothermic and exposed to two episodes of hypercapnia, there was no attenuation of cerebrovascular dilation during the second episode. They conclude that hypothermia reduces CBF secondarily to a decrease in cerebral metabolic rate and that percent dilator responsiveness to arterial hypercapnia is unaltered when body temperature is reduced.

  15. [Etiology of cerebral palsy].

    PubMed

    Jaisle, F

    1996-01-01

    The "perinatal asphyxia" is regarded to be one of the causes of cerebral palsy, though in the very most of the children with cerebral palsy there is found no hypoxia during labour. It should be mentioned, that the definition of "perinatal" and "asphyxia" neither are unic nor concret. And also there is no correlation between nonreassuring fetal heart rate patterns and acidosis in fetal blood with the incidence of cerebral palsy. Numerous studies in pregnant animals failed in proving an acute intrapartal hypoxia to be the origin of the cerebral palsy. Myers (1975) describes four patterns of anatomic brain damage after different injuries. Only his so called oligo-acidotic hypoxia, which is protracted and lasts over a longer time is leading to brain injury, which can be regarded in analogy to the injury of children with cerebral palsy. Summarising the update publications about the causes of cerebral palsy and the studies in pregnant animals there is no evidence that hypoxia during labour may be the cause of cerebral palsy. There is a great probability of a pre(and post-)natal origin of brain injury (for instance a periventricular leucomalacia found after birth) which leads to cerebral palsy. Short after labour signs of a so called "asphyxia" may occur in addition to this preexisting injury and misrepresent the cause of cerebral palsy. Finally the prepartal injury may cause both: Cerebral palsy and hypoxia. PMID:9035826

  16. Effects of amyloid and small vessel disease on white matter network disruption.

    PubMed

    Kim, Hee Jin; Im, Kiho; Kwon, Hunki; Lee, Jong Min; Ye, Byoung Seok; Kim, Yeo Jin; Cho, Hanna; Choe, Yearn Seong; Lee, Kyung Han; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Na, Duk L; Seo, Sang Won

    2015-01-01

    There is growing evidence that the human brain is a large scale complex network. The structural network is reported to be disrupted in cognitively impaired patients. However, there have been few studies evaluating the effects of amyloid and small vessel disease (SVD) markers, the common causes of cognitive impairment, on structural networks. Thus, we evaluated the association between amyloid and SVD burdens and structural networks using diffusion tensor imaging (DTI). Furthermore, we determined if network parameters predict cognitive impairments. Graph theoretical analysis was applied to DTI data from 232 cognitively impaired patients with varying degrees of amyloid and SVD burdens. All patients underwent Pittsburgh compound-B (PiB) PET to detect amyloid burden, MRI to detect markers of SVD, including the volume of white matter hyperintensities and the number of lacunes, and detailed neuropsychological testing. The whole-brain network was assessed by network parameters of integration (shortest path length, global efficiency) and segregation (clustering coefficient, transitivity, modularity). PiB retention ratio was not associated with any white matter network parameters. Greater white matter hyperintensity volumes or lacunae numbers were significantly associated with decreased network integration (increased shortest path length, decreased global efficiency) and increased network segregation (increased clustering coefficient, increased transitivity, increased modularity). Decreased network integration or increased network segregation were associated with poor performances in attention, language, visuospatial, memory, and frontal-executive functions. Our results suggest that SVD alters white matter network integration and segregation, which further predicts cognitive dysfunction. PMID:25374100

  17. Thioflavin T-Silent Denaturation Intermediates Support the Main-Chain-Dominated Architecture of Amyloid Fibrils.

    PubMed

    Noda, Sayaka; So, Masatomo; Adachi, Masayuki; Kardos, József; Akazawa-Ogawa, Yoko; Hagihara, Yoshihisa; Goto, Yuji

    2016-07-19

    Ultrasonication is considered one of the most effective agitations for inducing the spontaneous formation of amyloid fibrils. When we induced the ultrasonication-dependent fibrillation of β2-microglobulin and insulin monitored by amyloid-specific thioflavin T (ThT) fluorescence, both proteins showed a significant decrease in ThT fluorescence after the burst-phase increase. The decrease in ThT fluorescence was accelerated when the ultrasonic power was stronger, suggesting that this decrease was caused by the partial denaturation of preformed fibrils. The possible intermediates of denaturation retained amyloid-like morphologies, secondary structures, and seeding potentials. Similar denaturation intermediates were also observed when fibrils were denatured by guanidine hydrochloride or sodium dodecyl sulfate. The presence of these denaturation intermediates is consistent with the main-chain-dominated architecture of amyloid fibrils. Moreover, in the three types of denaturation experiments conducted, insulin fibrils were more stable than β2-microglobulin fibrils, suggesting that the relative stability of various fibrils is independent of the method of denaturation. PMID:27345358

  18. Beyond Amyloid: Getting Real about Non-Amyloid Targets in Alzheimer’s Disease

    PubMed Central

    Herrup, Karl; Carrillo, Maria; Schenk, Dale; Cacace, Angela; DeSanti, Susan; Fremeau, Robert; Bhat, Ratan; Glicksman, Marcie; May, Patrick; Swerdlow, Russell; van Eldik, Linda; Bain, Lisa J.; Budd, Samantha

    2014-01-01

    For decades, researchers have focused primarily on a pathway initiated by beta-amyloid (Aβ) aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early in the course of disease, even prior to the onset of clinical symptoms; thus, targeting amyloid in mild-to-moderate patients, as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer’s Association’s Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multi-factorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies. PMID:23809366

  19. The Role of the 14–20 Domain of the Islet Amyloid Polypeptide in Amyloid Formation

    PubMed Central

    Gilead, Sharon; Gazit, Ehud

    2008-01-01

    The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP) has been intensively studied since its identification in the late 1980s. The IAPP(20–29) region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29) in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils. PMID:18566678

  20. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    PubMed

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  1. A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain

    PubMed Central

    Diem, Alexandra K.; Tan, Mingyi; Bressloff, Neil W.; Hawkes, Cheryl; Morris, Alan W. J.; Weller, Roy O.; Carare, Roxana O.

    2016-01-01

    The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy. PMID:26903861

  2. AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism*

    PubMed Central

    Vingtdeux, Valérie; Giliberto, Luca; Zhao, Haitian; Chandakkar, Pallavi; Wu, Qingli; Simon, James E.; Janle, Elsa M.; Lobo, Jessica; Ferruzzi, Mario G.; Davies, Peter; Marambaud, Philippe

    2010-01-01

    Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Aβ levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Aβ metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-β. Direct pharmacological and genetic activation of AMPK lowered extracellular Aβ accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Aβ levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Aβ. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Aβ levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease. PMID:20080969

  3. A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain.

    PubMed

    Diem, Alexandra K; Tan, Mingyi; Bressloff, Neil W; Hawkes, Cheryl; Morris, Alan W J; Weller, Roy O; Carare, Roxana O

    2016-01-01

    The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy. PMID:26903861

  4. Posttherapeutic cerebral radionecrosis: a complication of head and neck tumor therapy

    SciTech Connect

    Araoz, C.; Weems, A.M.

    1981-12-01

    Patients with treated head and neck cancer may have focal neurologic symptoms and personality changes due to delayed cerebral radionecrosis. A history of past treatment should direct the physician to consider these lesions in the differential diagnosis. Craniotomy is the management recommended. Histopathologic changes include fibrotic response of the meninges with pleomorphic and vacuolated fibroblasts, capillary hyperplasia, reactive astrocytes, and fibrosis of the blood vessels. Amyloid is deposited in the arteriolar walls and extracellular space. Ischemic, autoimmune, or vascular mechanisms, and glial alterations have all been considered in the pathogensis of delayed cerebral radionecrosis. Some researchers have concluded that chemotherapeutic agents, such as methotrexate, may contribute to its production.

  5. Contemporary treatment of amyloid heart disease.

    PubMed

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  6. Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

    PubMed Central

    Tamayev, Robert; Matsuda, Shuji; Fà, Mauro; Arancio, Ottavio; D’Adamio, Luciano

    2010-01-01

    According to the prevailing “amyloid cascade hypothesis,” genetic dementias such as Alzheimer’s disease and familial Danish dementia (FDD) are caused by amyloid deposits that trigger tauopathy, neurodegeneration, and behavioral/cognitive alterations. To efficiently reproduce amyloid lesions, murine models of human dementias invariably use transgenic expression systems. However, recent FDD transgenic models showed that Danish amyloidosis does not cause memory defects, suggesting that other mechanisms cause Danish dementia. We studied an animal knock-in model of FDD (FDDKI/+) genetically congruous with human cases. FDDKI/+ mice present reduced Bri2 levels, impaired synaptic plasticity and severe hippocampal memory deficits. These animals show no cerebral lesions that are reputed characteristics of human dementia, such as tangles or amyloid plaques. Bri2+/− mice exhibit synaptic and memory deficits similar to FDDKI/+ mice, and memory loss of FDDKI/+ mice is prevented by expression of WT BRI2, indicating that Danish dementia is caused by loss of BRI2 function. Together, the data suggest that clinical dementia in Danish patients occurs via a loss of function mechanism and not as a result of amyloidosis and tauopathy. PMID:21098268

  7. The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo.

    PubMed

    Mazzitelli, Sonia; Xu, Ping; Ferrer, Isidre; Davis, Roger J; Tournier, Cathy

    2011-11-23

    Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-β (Aβ), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Aβ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to Aβ. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in Aβ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for γ-mediated cleavage of the C-terminal fragment of APP produced by β-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD. PMID:22114267

  8. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto.

    PubMed

    Hsu, Ruei-Lin; Lee, Kung-Ta; Wang, Jung-Hao; Lee, Lily Y-L; Chen, Rita P-Y

    2009-01-28

    More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ordered protein aggregate with a lamellar cross-beta structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin. PMID:19117402

  9. A brief overview of amyloids and Alzheimer’s disease

    PubMed Central

    Ow, Sian-Yang; Dunstan, Dave E

    2014-01-01

    Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with a number of presently incurable diseases such as Alzheimer’s and Parkinson’s disease. Millions of people worldwide suffer from amyloid diseases. This review summarizes the unique cross-β structure of amyloid fibrils, morphological variations, the kinetics of amyloid fibril formation, and the cytotoxic effects of these fibrils and oligomers. Alzheimer’s disease is also explored as an example of an amyloid disease to show the various approaches to treat these amyloid diseases. Finally, this review investigates the nanotechnological and biological applications of amyloid fibrils; as well as a summary of the typical biological pathways involved in the disposal of amyloid fibrils and their precursors. PMID:25042050

  10. Physical and structural basis for polymorphism in amyloid fibrils

    PubMed Central

    Tycko, Robert

    2014-01-01

    As our understanding of the molecular structures of amyloid fibrils has matured over the past 15 years, it has become clear that, while amyloid fibrils do have well-defined molecular structures, their molecular structures are not uniquely determined by the amino acid sequences of their constituent peptides and proteins. Self-propagating molecular-level polymorphism is a common phenomenon. This article reviews current information about amyloid fibril structures, variations in molecular structures that underlie amyloid polymorphism, and physical considerations that explain the development and persistence of amyloid polymorphism. Much of this information has been obtained through solid state nuclear magnetic resonance measurements. The biological significance of amyloid polymorphism is also discussed briefly. Although this article focuses primarily on studies of fibrils formed by amyloid-β peptides, the same principles apply to many amyloid-forming peptides and proteins. PMID:25179159

  11. Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes

    PubMed Central

    2013-01-01

    Protein misfolding into amyloid-like aggregates underlies many neurodegenerative diseases. Thus, insights into the structure and function of these amyloids will provide valuable information on the pathological mechanisms involved and aid in the design of improved drugs for treating amyloid-based disorders. However, determining the structure of endogenous amyloids at high resolution has been difficult. Here we employ binding-activated localization microscopy (BALM) to acquire superresolution images of α-synuclein amyloid fibrils with unprecedented optical resolution. We propose that BALM imaging can be extended to study the structure of other amyloids, for differential diagnosis of amyloid-related diseases and for discovery of drugs that perturb amyloid structure for therapy. PMID:23594172

  12. Rapid Generation of Amyloid from Native Proteins In vitro

    PubMed Central

    Dorta-Estremera, Stephanie M; Li, Jingjing; Cao, Wei

    2013-01-01

    Proteins carry out crucial tasks in organisms by exerting functions elicited from their specific three dimensional folds. Although the native structures of polypeptides fulfill many purposes, it is now recognized that most proteins can adopt an alternative assembly of beta-sheet rich amyloid. Insoluble amyloid fibrils are initially associated with multiple human ailments, but they are increasingly shown as functional players participating in various important cellular processes. In addition, amyloid deposited in patient tissues contains nonproteinaceous components, such as nucleic acids and glycosaminoglycans (GAGs). These cofactors can facilitate the formation of amyloid, resulting in the generation of different types of insoluble precipitates. By taking advantage of our understanding how proteins misfold via an intermediate stage of soluble amyloid precursor, we have devised a method to convert native proteins to amyloid fibrils in vitro. This approach allows one to prepare amyloid in large quantities, examine the properties of amyloid generated from specific proteins, and evaluate the structural changes accompanying the conversion. PMID:24335677

  13. Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif.

    PubMed

    Jacob, Reeba S; George, Edna; Singh, Pradeep K; Salot, Shimul; Anoop, Arunagiri; Jha, Narendra Nath; Sen, Shamik; Maji, Samir K

    2016-03-01

    Amyloids are highly ordered, cross-β-sheet-rich protein/peptide aggregates associated with both human diseases and native functions. Given the well established ability of amyloids in interacting with cell membranes, we hypothesize that amyloids can serve as universal cell-adhesive substrates. Here, we show that, similar to the extracellular matrix protein collagen, amyloids of various proteins/peptides support attachment and spreading of cells via robust stimulation of integrin expression and formation of integrin-based focal adhesions. Additionally, amyloid fibrils are also capable of immobilizing non-adherent red blood cells through charge-based interactions. Together, our results indicate that both active and passive mechanisms contribute to adhesion on amyloid fibrils. The present data may delineate the functional aspect of cell adhesion on amyloids by various organisms and its involvement in human diseases. Our results also raise the exciting possibility that cell adhesivity might be a generic property of amyloids. PMID:26742841

  14. MicroRNA-384 regulates both amyloid precursor protein and β-secretase expression and is a potential biomarker for Alzheimer's disease.

    PubMed

    Liu, Chen-Geng; Wang, Jin-Ling; Li, Lei; Wang, Pei-Chang

    2014-07-01

    Amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE-1) play important roles in the pathogenesis of Alzheimer's disease (AD). In this study, using bioinformatics analysis, we demonstrate that miR-384 is a microRNA (miRNA or miR) predicted to potentially target the 3' untranslated regions (3'-UTRs) of both APP and BACE-1. SH-SY5Y cells were transfected with miR-384 mimic oligonucleotide, miR-384 inhibitor oligonucleotide, or a non-specific control siRNA. We found that the overexpression of miR-384 suppressed the mRNA and protein expression of both APP and BACE-1. The miR-384 inhibitor oligonucleotide induced the upregulation of APP and BACE-1. The activity of BACE-1 was altered following the change in its protein expression. The binding sites of miR-384 on the 3'-UTRs of APP and BACE-1 were identified by luciferase assay. Furthermore, cells were treasted with amyloid-β (Aβ)42. Aβ42 downregulated miR-384 expression, leading to the continuous reduction in miR-384 expression. In addition, using a mouse model of AD, as well as patients with mild cognitive impairment (MCI) and dementia of Alzheimer's type (DAT), we examined the levels of miR-384 in cerebral spinal fluid (CSF) and serum. Patients with MCI and DAT had lower blood miR-384 levels compared with the controls. In addition, patients with DAT had lower blood miR-384 levels in blood compared with the MCI group. We also found decreased miR-384 expression in the several cerebral spinal fluid (CSF) of the patients with DAT. Negative correlations were observed between miR-384 and Aβ42 in the serum and CSF from patients with AD. In conclusion, these findings demonstrate that miR-384 may plays a role in the development of AD and may be a potential non-invasive biomarker for the diagnosis of AD. PMID:24827165

  15. Hemiparesis post cerebral malaria

    PubMed Central

    Taiaa, Oumkaltoum; Amil, Touriya; Darbi, Abdelatif

    2015-01-01

    Cerebral malaria is one of the most serious complications in the Plasmodium falciparum infection. In endemic areas, the cerebral malaria interested mainly children. The occurrence in adults is very rare and most interested adult traveling in tropical zones. This case report describes a motor deficit post cerebral malaria in a young adult traveling in malaria endemic area. This complication has been reported especially in children and seems very rare in adults. PMID:25995798

  16. Investigation of the inhibitory effects of TiO(2) on the β-amyloid peptide aggregation.

    PubMed

    Ahmed, Mukhtar H; Byrne, John A; Keyes, Tia E

    2014-06-01

    TiO2 thin films are of great interest as biocompatible coatings and also as photocatalytic self-cleaning and antimicrobial coatings. In this work we used β-amyloid as a model for infectious protein to investigate the attachment and photocatalytic degradation. TiO2 films were prepared on stainless steel substrates using magnetron sputtering. The films were characterised before and after exposure to β-amyloid (1-42), using XRD, Raman spectroscopy, XPS and AFM. The TiO2 film was mostly composed of the anatase phase with a relatively high surface roughness. The presence of Raman peaks at 1668cm(-1) and 1263cm(-1), with the XPS spectral feature for nitrogen at 400eV, confirmed the adsorption of amyloid on surface. Following exposure of the β-amyloid contaminated TiO2 to UV-B irradiation a slight shift of amide modes was observed. Furthermore, the amide I spectra show an overall decrease in α-helix content with presence of a minor peak around 1591cm(-1), which is related to tryptophanyl and tyrosinyl radicals, which can lead to conformational change of β-amyloid. The C1s band at 292.2eV suggests the formation of free carboxylic acid. The loss in the crucial structure of β-amyloid leads to reduce the fibril formation, thought to be induced through a photocatalytic process. PMID:24863220

  17. Occurrence of extensive spherical amyloid deposits in a prolactin-secreting pituitary macroadenoma: a radiologic-pathologic correlation.

    PubMed

    Levine, Steven N; Ishaq, Shmaila; Nanda, Anil; Wilson, Jon D; Gonzalez-Toledo, Eduardo

    2013-08-01

    Pituitary adenomas are the most common tumors of the sellar region, but the occurrence of spherical amyloid deposits in a pituitary adenoma is rare. We describe the clinical features, radiologic characteristics, and pathologic findings of 45-year-old man who presented with galactorrhea, hypogonadism, and hyperprolactinemia who had a pituitary adenoma with extensive spherical amyloid deposits. Approximately 30 cases have been reported, almost exclusively in patients with prolactinomas. Treatment with dopaminergic agonists will result in the expected reduction in prolactin levels; however, in most cases, macroadenomas with spherical amyloid deposits fail to decrease in size. The source of the amyloid deposits in prolactinomas is not clearly defined but may be due to abnormal processing of prolactin or its prohormone. These adenomas with spherical amyloid have a characteristic appearance on magnetic resonance imaging with low or heterogeneous intensity on T1 and low intensity on T2-weighted images. Following infusion of gadolinium, there is enhancement of the periphery but not most of the tumor mass. These magnetic resonance imaging characteristics are different than those of typical pituitary adenomas. These differences should alert clinicians to the possibility of extensive spherical amyloid deposits in a prolactin-secreting pituitary adenoma, which may have important clinical implications. In this report, we correlate the radiologic finds with the pathology and compared them with other sellar and parasellar lesions. PMID:23602507

  18. On the Heat Stability of Amyloid-Based Biological Activity: Insights from Thermal Degradation of Insulin Fibrils

    PubMed Central

    Surmacz-Chwedoruk, Weronika; Malka, Iwona; Bożycki, Łukasz; Nieznańska, Hanna; Dzwolak, Wojciech

    2014-01-01

    Formation of amyloid fibrils in vivo has been linked to disorders such as Alzheimer’s disease and prion-associated transmissible spongiform encephalopathies. One of the characteristic features of amyloid fibrils is the high thermodynamic stability relative both to native and disordered states which is also thought to underlie the perplexingly remarkable heat resistance of prion infectivity. Here, we are comparing high-temperature degradation of native and fibrillar forms of human insulin. Decomposition of insulin amyloid has been studied under helium atmosphere and in the temperature range from ambient conditions to 750°C using thermogravimetry and differential scanning calorimetry coupled to mass spectrometry. While converting native insulin into amyloid does upshift onset of thermal decomposition by ca. 75°C, fibrils remain vulnerable to covalent degradation at temperatures below 300°C, as reflected by mass spectra of gases released upon heating of amyloid samples, as well as morphology and infrared spectra of fibrils subjected to incubation at 250°C. Mass spectra profiles of released gases indicate that degradation of fibrils is much more cooperative than degradation of native insulin. The data show no evidence of water of crystallization trapped within insulin fibrils. We have also compared untreated and heated amyloid samples in terms of capacity to seed daughter fibrils. Kinetic traces of seed-induced insulin fibrillation have shown that the seeding potency of amyloid samples decreases significantly already after exposure to 200°C, even though corresponding electron micrographs indicated persisting fibrillar morphology. Our results suggest that amyloid-based biological activity may not survive extremely high temperature treatments, at least in the absence of other stabilizing factors. PMID:24466022

  19. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's disease.

    PubMed

    Fan, Zhen; Okello, Aren A; Brooks, David J; Edison, Paul

    2015-12-01

    Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer

  20. Appropriate Use Criteria for Amyloid PET

    PubMed Central

    Johnson, Keith A.; Minoshima, Satoshi; Bohnen, Nicolaas I.; Donohoe, Kevin J.; Foster, Norman L.; Herscovitch, Peter; Karlawish, Jason H.; Rowe, Christopher C.; Carrillo, Maria C.; Hartley, Dean M.; Hedrick, Saima; Mitchell, Kristi; Pappas, Virginia; Thies, William H.

    2013-01-01

    Positron Emission Tomography (PET) of brain amyloid-beta is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. In order to provide guidance to dementia care practitioners, patients and caregivers, the Alzheimer Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be appropriately used. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. While empirical evidence of impact on clinical outcomes is not yet available, a set of specific Appropriate Use Criteria (AUC) were agreed upon that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID:23360977

  1. Shear flow promotes amyloid-{beta} fibrilization.

    PubMed

    Dunstan, Dave E; Hamilton-Brown, Paul; Asimakis, Peter; Ducker, William; Bertolini, Joseph

    2009-12-01

    The rate of formation of amyloid fibrils in an aqueous solution of amyloid-beta (Abeta) is greatly increased when the solution is sheared. When Abeta solution is stirred with a magnetic stirrer bar at 37 degrees C, a rapid increase in thioflavin T fluorescence is observed. Atomic Force Microscopy (AFM) images show the formation of aggregates, the growth of fibrils and the intertwining of the fibrils with time. Circular dichroism (CD) spectroscopy of samples taken after stirring shows a transition from random coil to alpha-helix to beta-sheet secondary structure over 20 h at 37 degrees C. The fluorescence, AFM and CD measurements are all consistent with the formation of amyloid fibrils. Quiescent, non-stirred solutions incubated at 37 degrees C showed no evidence of amyloid formation over a period of 3 days. Couette flow was found to accelerate the formation of amyloid fibrils demonstrating that the primary effect of stirring is not mixing but shearing. Only very small shear forces are applied to individual molecules in our experiments. Simple calculation suggests that the force is too small to support a hypothesis that shearing promotes partial unfolding of the protein as is observed. PMID:19850675

  2. Functional Amyloids in the Mouse Sperm Acrosome

    PubMed Central

    Guyonnet, Benoit; Egge, Nathan

    2014-01-01

    The acrosomal matrix (AM) is an insoluble structure within the sperm acrosome that serves as a scaffold controlling the release of AM-associated proteins during the sperm acrosome reaction. The AM also interacts with the zona pellucida (ZP) that surrounds the oocyte, suggesting a remarkable stability that allows its survival despite being surrounded by proteolytic and hydrolytic enzymes released during the acrosome reaction. To date, the mechanism responsible for the stability of the AM is not known. Our studies demonstrate that amyloids are present within the sperm AM and contribute to the formation of an SDS- and formic-acid-resistant core. The AM core contained several known amyloidogenic proteins, as well as many proteins predicted to form amyloid, including several ZP binding proteins, suggesting a functional role for the amyloid core in sperm-ZP interactions. While stable at pH 3, at pH 7, the sperm AM rapidly destabilized. The pH-dependent dispersion of the AM correlated with a change in amyloid structure leading to a loss of mature forms and a gain of immature forms, suggesting that the reversal of amyloid is integral to AM dispersion. PMID:24797071

  3. Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARγ involvement.

    PubMed

    Scuderi, Caterina; Steardo, Luca; Esposito, Giuseppe

    2014-07-01

    The amyloidogenic cascade is regarded as a key factor at the basis of Alzheimer's disease (AD) pathogenesis. The aberrant cleavage of amyloid precursor protein (APP) induces an increased production and a subsequent aggregation of beta amyloid (Aβ) peptide in limbic and association cortices. As a result, altered neuronal homeostasis and oxidative injury provoke tangle formation with consequent neuronal loss. Cannabidiol (CBD), a Cannabis derivative devoid of psychotropic effects, has attracted much attention because it may beneficially interfere with several Aβ-triggered neurodegenerative pathways, even though the mechanism responsible for such actions remains unknown. In the present research, the role of CBD was investigated as a possible modulating compound of APP processing in SHSY5Y(APP+) neurons. In addition, the putative involvement of peroxisome proliferator-activated receptor-γ (PPARγ) was explored as a candidate molecular site responsible for CBD actions. Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate. Obtained results also showed that all, here observed, CBD effects were dependent on the selective activation of PPARγ. PMID:24288245

  4. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice.

    PubMed

    Yan, Ping; Bero, Adam W; Cirrito, John R; Xiao, Qingli; Hu, Xiaoyan; Wang, Yan; Gonzales, Ernesto; Holtzman, David M; Lee, Jin-Moo

    2009-08-26

    Amyloid plaques are primarily composed of extracellular aggregates of amyloid-beta (Abeta) peptide and are a pathological signature of Alzheimer's disease. However, the factors that influence the dynamics of amyloid plaque formation and growth in vivo are largely unknown. Using serial intravital multiphoton microscopy through a thinned-skull cranial window in APP/PS1 transgenic mice, we found that amyloid plaques appear and grow over a period of weeks before reaching a mature size. Growth was more prominent early after initial plaque formation: plaques grew faster in 6-month-old compared with 10-month-old mice. Plaque growth rate was also size-related, as smaller plaques exhibited more rapid growth relative to larger plaques. Alterations in interstitial Abeta concentrations were associated with changes in plaque growth. Parallel studies using multiphoton microscopy and in vivo microdialysis revealed that pharmacological reduction of soluble extracellular Abeta by as little as 20-25% was associated with a dramatic decrease in plaque formation and growth. Furthermore, this small reduction in Abeta synthesis was sufficient to reduce amyloid plaque load in 6-month-old but not 10-month-old mice, suggesting that treatment early in disease pathogenesis may be more effective than later treatment. In contrast to thinned-skull windows, no significant plaque growth was observed under open-skull windows, which demonstrated extensive microglial and astrocytic activation. Together, these findings indicate that individual amyloid plaque growth in vivo occurs over a period of weeks and may be influenced by interstitial Abeta concentration as well as reactive gliosis. PMID:19710322

  5. Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and Toxicity

    PubMed Central

    Lee, Young Jin; Savtchenko, Regina; Ostapchenko, Valeriy G.; Makarava, Natallia; Baskakov, Ilia V.

    2011-01-01

    Background According to the prevailing view, soluble oligomers or small fibrillar fragments are considered to be the most toxic species in prion diseases. To test this hypothesis, two conformationally different amyloid states were produced from the same highly pure recombinant full-length prion protein (rPrP). The cytotoxic potential of intact fibrils and fibrillar fragments generated by sonication from these two states was tested using cultured cells. Methodology/Principal Findings For one amyloid state, fibril fragmentation was found to enhance its cytotoxic potential, whereas for another amyloid state formed within the same amino acid sequence, the fragmented fibrils were found to be substantially less toxic than the intact fibrils. Consistent with the previous studies, the toxic effects were more pronounced for cell cultures expressing normal isoform of the prion protein (PrPC) at high levels confirming that cytotoxicity was in part PrPC-dependent. Silencing of PrPC expression by small hairpin RNAs designed to silence expression of human PrPC (shRNA-PrPC) deminished the deleterious effects of the two amyloid states to a different extent, suggesting that the role of PrPC-mediated and PrPC-independent mechanisms depends on the structure of the aggregates. Conclusions/Significance This work provides a direct illustration that the relationship between an amyloid's physical dimension and its toxic potential is not unidirectional but is controlled by the molecular structure of prion protein (PrP) molecules within aggregated states. Depending on the structure, a decrease in size of amyloid fibrils can either enhance or abolish their cytotoxic effect. Regardless of the molecular structure or size of PrP aggregates, silencing of PrPC expression can be exploited to reduce their deleterious effects. PMID:21625461

  6. Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis*

    PubMed Central

    Oskarsson, Marie E.; Singh, Kailash; Wang, Jian; Vlodavsky, Israel; Li, Jin-ping; Westermark, Gunilla T.

    2015-01-01

    Deposition of β cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mm glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that β cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of β cells. PMID:25922077

  7. Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice.

    PubMed

    Wu, Zhen; Yang, Bin; Liu, Chunxia; Liang, Ge; Liu, Weixia; Pickup, Stephen; Meng, Qingcheng; Tian, Yuke; Li, Shitong; Eckenhoff, Maryellen F; Wei, Huafeng

    2015-01-01

    In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition. PMID:25650693

  8. Structure of amyloid oligomers and their mechanisms of toxicities: Targeting amyloid oligomers using novel therapeutic approaches.

    PubMed

    Salahuddin, Parveen; Fatima, Munazza Tamkeen; Abdelhameed, Ali Saber; Nusrat, Saima; Khan, Rizwan Hasan

    2016-05-23

    Protein misfolding is one of the leading causes of amyloidoses. Protein misfolding occurs from changes in environmental conditions and host of other factors, including errors in post-translational modifications, increase in the rate of degradation, error in trafficking, loss of binding partners and oxidative damage. Misfolding gives rise to the formation of partially unfolded or misfolded intermediates, which have exposed hydrophobic residues and interact with complementary intermediates to form oligomers and consequently protofibrils and fibrils. The amyloid fibrils accumulate as amyloid deposits in the brain and central nervous system in Alzheimer's disease (AD), Prion disease and Parkinson's disease (PD). Initial studies have shown that amyloid fibrils were the main culprit behind toxicity that cause neurodegenerative diseases. However, attention shifted to the cytotoxicity of amyloid fibril precursors, notably amyloid oligomers, which are the major cause of toxicity. The mechanism of toxicity triggered by amyloid oligomers remains elusive. In this review, we have focused on the current knowledge of the structures of different aggregated states, including amyloid fibril, protofibrils, annular aggregates and oligomers. Based on the studies on the mechanism of toxicities, we hypothesize two major possible mechanisms of toxicities instigated by oligomers of Aβ (amyloid beta), PrP (prion protein) (106-126), and α-Syn (alpha-synuclein) including direct formation of ion channels and neuron membrane disruption by the increase in membrane conductance or leakage in the presence of small globulomers to large prefibrillar assemblies. Finally, we have discussed various novel innovative approaches that target amyloid oligomers in Alzheimer's diseases, Prion disease and Parkinson's disease. PMID:26974374

  9. Cerebral Asymmetries and Reading Acquisition

    ERIC Educational Resources Information Center

    Pirozzolo, Francis J.

    1978-01-01

    Reviewed are historical developments regarding the concepts of cerebral localization, and analyzed are implications of current research on the role of the cerebral hemispheres in reading disorders. (CL)

  10. Can Alzheimer disease be prevented by amyloid-β immunotherapy?

    PubMed Central

    Lemere, Cynthia A.; Masliah, Eliezer

    2010-01-01

    Alzheimer disease (AD) is the most common form of dementia. The amyloid-β (Aβ) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Aβ immunotherapies have been shown to lower cerebral Aβ levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Aβ vaccine was stopped when ~6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Aβ immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Aβ vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Aβ immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Aβ immunization. PMID:20140000

  11. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children

    PubMed Central

    Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Cross, Janet V.; Engle, Randall; Aragón-Flores, Mariana; Gómez-Garza, Gilberto; Jewells, Valerie; Weili, Lin; Medina-Cortina, Humberto; Solorio, Edelmira; Chao, Chih-kai; Zhu, Hongtu; Mukherjee, Partha S.; Ferreira-Azevedo, Lara; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

    2013-01-01

    Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9–24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer's and Parkinson's diseases. PMID:23986703

  12. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children.

    PubMed

    Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Cross, Janet V; Engle, Randall; Aragón-Flores, Mariana; Gómez-Garza, Gilberto; Jewells, Valerie; Medina-Cortina, Humberto; Solorio, Edelmira; Chao, Chih-Kai; Zhu, Hongtu; Mukherjee, Partha S; Ferreira-Azevedo, Lara; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

    2013-01-01

    Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9-24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer's and Parkinson's diseases. PMID:23986703

  13. Fibrillar dimer formation of islet amyloid polypeptides

    NASA Astrophysics Data System (ADS)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  14. Fibrillar dimer formation of islet amyloid polypeptides

    SciTech Connect

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  15. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity.

    PubMed

    Du, Wen-Jie; Guo, Jing-Jing; Gao, Ming-Tao; Hu, Sheng-Quan; Dong, Xiao-Yan; Han, Yi-Fan; Liu, Fu-Feng; Jiang, Shaoyi; Sun, Yan

    2015-01-01

    Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 ± 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease. PMID:25613018

  16. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

    NASA Astrophysics Data System (ADS)

    Du, Wen-Jie; Guo, Jing-Jing; Gao, Ming-Tao; Hu, Sheng-Quan; Dong, Xiao-Yan; Han, Yi-Fan; Liu, Fu-Feng; Jiang, Shaoyi; Sun, Yan

    2015-01-01

    Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 +/- 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

  17. Compressive deformation of ultralong amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Paparcone, Raffaella; Cranford, Steven; Buehler, Markus J.

    2010-12-01

    Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale. At the atomistic level, a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa, larger than many other biological nanofibrils, a result confirmed by both experiment and theory. However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown. Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril, extends to the mesoscale level, reaching size scales of hundreds of nanometers. We use parameters directly derived from full atomistic simulations of A β (1-40) amyloid fibrils to parameterize a mesoscopic coarse-grained model, which is used to reproduce the elastic properties of amyloid fibrils. We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling, an effect that could be important to interpret experimental results of ultra-long amyloid fibrils. Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior. The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.

  18. [Treatment of familial amyloid polyneuropathy].

    PubMed

    Adams, David; Samuel, Didier; Slama, Michel

    2012-09-01

    The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the

  19. Cerebral Palsy (CP) Quiz

    MedlinePlus

    ... Submit Button Past Emails CDC Features Pop Quiz: Cerebral Palsy Language: English Español (Spanish) Recommend on Facebook Tweet ... Sandy is the parent of a child with cerebral palsy and the Board President of Gio’s Garden , a ...

  20. [Familial amyloid polyneuropathies: therapeutic issues].

    PubMed

    Adams, David; Cauquil, Cécile; Théaudin, Marie

    2012-10-01

    Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner. PMID:23815018

  1. Amyloid growth: combining experiment and kinetic theory

    NASA Astrophysics Data System (ADS)

    Knowles, Tuomas; Cohen, Samuel; Vendruscolo, Michele; Dobson, Christopher

    2012-02-01

    The conversion of proteins from their soluble forms into fibrillar amyloid nanostructures is a general type of behaviour encountered for many different proteins in the context of disease as well as for the generation of a select class of functional materials in nature. This talk focuses on the problem of defining the rates of the individual molecular level processes involved in the overall conversion reaction. A master equation approach is discussedootnotetextCohen et al, J Chem Phys 2011, 135, 065106 ootnotetextKnowles et al, Science, 2009, 326, 1533-1537 and used in combination with kinetic measurements to yield mechanistic insights into the amyloid growth phenomenon.

  2. Amyloids or prions? That is the question

    PubMed Central

    Sabate, Raimon; Rousseau, Frederic; Schymkowitz, Joost; Batlle, Cristina; Ventura, Salvador

    2015-01-01

    ABSTRACT Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation. PMID:26039159

  3. Quenched Hydrogen Exchange NMR of Amyloid Fibrils.

    PubMed

    Alexandrescu, Andrei T

    2016-01-01

    Amyloid fibrils are associated with a number of human diseases. These aggregatively misfolded intermolecular β-sheet assemblies constitute some of the most challenging targets in structural biology because to their complexity, size, and insolubility. Here, protocols and controls are described for experiments designed to study hydrogen-bonding in amyloid fibrils indirectly, by transferring information about amide proton occupancy in the fibrils to the dimethyl sulfoxide-denatured state. Since the denatured state is amenable to solution NMR spectroscopy, the method can provide residue-level-resolution data on hydrogen exchange for the monomers that make up the fibrils. PMID:26453215

  4. Longitudinal study of cerebrospinal fluid amyloid proteins and apolipoprotein E in patients with probable Alzheimer's disease.

    PubMed

    Pirttilä, T; Koivisto, K; Mehta, P D; Reinikainen, K; Kim, K S; Kilkku, O; Heinonen, E; Soininen, H; Riekkinen, P; Wisniewski, H M

    1998-06-12

    Levels of soluble amyloid beta protein (sAbeta), amyloid beta precursor protein (APP) and apolipoprotein E (apoE) were examined in cerebrospinal fluid (CSF) obtained twice, at baseline and after 3-year follow-up, from 25 patients with probable Alzheimer's disease (AD). Levels of sAbeta and apoE from patients with the apoE4 allele decreased with time, whereas the levels were similar in patients without apoE4 allele. Changes of sAbeta and apoE concentrations correlated significantly with those of mini-mental state examination (MMSE) scores. Levels of sAbeta did not change with time in patients with mild dementia, whereas they decreased significantly in patients with moderate dementia. ApoE concentrations decreased in both groups whereas APP levels were similar. We conclude that measurements of CSF sAbeta and apoE levels may be helpful in monitoring progression of the disease. PMID:9672379

  5. Is Vasomotion in Cerebral Arteries Impaired in Alzheimer’s Disease?

    PubMed Central

    Di Marco, Luigi Yuri; Farkas, Eszter; Martin, Chris; Venneri, Annalena; Frangi, Alejandro F.

    2015-01-01

    Abstract A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer’s disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion— the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain— is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Aβ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Aβ clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Aβ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Aβ and oxidative stress accumulation. PMID:25720414

  6. Characterization of a Novel Mouse Model of Alzheimer’s Disease—Amyloid Pathology and Unique β-Amyloid Oligomer Profile

    PubMed Central

    Liu, Peng; Paulson, Jennifer B.; Forster, Colleen L.; Shapiro, Samantha L.; Ashe, Karen H.; Zahs, Kathleen R.

    2015-01-01

    Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzheimer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APPNLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APPNLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology—such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation—was observed in the vicinity of neuritic plaques. Biochemically, we determined total Aβ production at varied ages of mice, and we showed that mice produced primarily fibrillar Aβ assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., Aβ*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar Aβ assemblies in situ. PMID:25946042

  7. Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers.

    PubMed

    Umeda, Tomohiro; Ono, Kenjiro; Sakai, Ayumi; Yamashita, Minato; Mizuguchi, Mineyuki; Klein, William L; Yamada, Masahito; Mori, Hiroshi; Tomiyama, Takami

    2016-05-01

    /day for 1 month decreased amyloid-β oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14-15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer's disease and other neurodegenerative diseases. PMID:27020329

  8. Hemodynamic and metabolic effects of cerebral revascularization.

    PubMed

    Leblanc, R; Tyler, J L; Mohr, G; Meyer, E; Diksic, M; Yamamoto, L; Taylor, L; Gauthier, S; Hakim, A

    1987-04-01

    Pre- and postoperative positron emission tomography (PET) was performed in six patients undergoing extracranial to intracranial bypass procedures for the treatment of symptomatic extracranial carotid occlusion. The six patients were all men, aged 52 to 68 years. Their symptoms included transient ischemic attacks (five cases), amaurosis fugax (two cases), and completed stroke with good recovery (one case). Positron emission tomography was performed within 4 weeks prior to surgery and between 3 to 6 months postoperatively, using oxygen-15-labeled CO, O2, and CO2 and fluorine-18-labeled fluorodeoxyglucose. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rates for oxygen and glucose (CMRO2 and CMRGlu), and the oxygen extraction fraction (OEF) were measured in both hemispheres. Preoperatively, compared to five elderly control subjects, patients had increased CBV, a decreased CBF/CBV ratio, and decreased CMRO2, indicating reduced cerebral perfusion pressure and depressed oxygen metabolism. The CBF was decreased in only one patient who had bilateral carotid occlusions; the OEF, CMRGlu, and CMRO2/CMRGlu and CMRGlu/CBF ratios were not significantly different from control measurements. All bypasses were patent and all patients were asymptomatic following surgery. Postoperative PET revealed decreased CBV and an increased CBF/CBV ratio, indicating improved hemodynamic function and oxygen hypometabolism. This was associated with increased CMRO2 in two patients in whom the postoperative OEF was also increased. The CMRGlu and CMRGlu/CBF ratio were increased in five patients. Changes in CBF and the CMRO2/CMRGlu ratio were variable. One patient with preoperative progressive mental deterioration, documented by serial neuropsychological testing and decreasing CBF and CMRO2, had improved postoperative CBF and CMRO2 concomitant with improved neuropsychological functioning. It is concluded that symptomatic carotid occlusion is associated with altered

  9. Relationship between cerebral sodium-glucose transporter and hyperglycemia in cerebral ischemia.

    PubMed

    Yamazaki, Yui; Harada, Shinichi; Tokuyama, Shogo

    2015-09-14

    Post-ischemic hyperglycemia exacerbates the development of cerebral ischemia. To elucidate this exacerbation mechanism, we focused on sodium-glucose transporter (SGLT) as a mediator that lead hyperglycemia to cerebral ischemia. SGLT transport glucose into the cell, together with sodium ion, using the sodium concentration gradient. We have previously reported that suppression of cerebral SGLT ameliorates cerebral ischemic neuronal damage. However, detail relationship cerebral between SGLT and post-ischemic hyperglycemia remain incompletely defined. Therefore, we examined the involvement of cerebral SGLT on cerebral ischemic neuronal damage with or without hyperglycemic condition. Cell survival rate of primary cultured neurons was assessed by biochemical assay. A mouse model of focal ischemia was generated using a middle cerebral artery occlusion (MCAO). Neuronal damage was assessed with histological and behavioral analyses. Concomitant hydrogen peroxide/glucose treatment exacerbated hydrogen peroxide alone-induced cell death. Although a SGLT family-specific inhibitor, phlorizin had no effect on developed hydrogen peroxide alone-induced cell death, it suppressed cell death induced by concomitant hydrogen peroxide/glucose treatment. α-MG induced a concentration-dependent and significant decrease in neuronal survival. PHZ administered on immediately after reperfusion had no effect, but PHZ given at 6h after reperfusion had an effect. Our in vitro study indicates that SGLT is not involved in neuronal cell death in non-hyperglycemic condition. We have already reported that post-ischemic hyperglycemia begins to develop at 6h after MCAO. Therefore, current our in vivo study show post-ischemic hyperglycemic condition may be necessary for the SGLT-mediated exacerbation of cerebral ischemic neuronal damage. PMID:26254165

  10. PARP-1 modulates amyloid beta peptide-induced neuronal damage.

    PubMed

    Martire, Sara; Fuso, Andrea; Rotili, Dante; Tempera, Italo; Giordano, Cesare; De Zottis, Ivana; Muzi, Alessia; Vernole, Patrizia; Graziani, Grazia; Lococo, Emanuela; Faraldi, Martina; Maras, Bruno; Scarpa, Sigfrido; Mosca, Luciana; d'Erme, Maria

    2013-01-01

    Amyloid beta peptide (Aβ) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed. PMID:24086258

  11. PARP-1 Modulates Amyloid Beta Peptide-Induced Neuronal Damage

    PubMed Central

    Martire, Sara; Fuso, Andrea; Rotili, Dante; Tempera, Italo; Giordano, Cesare; De Zottis, Ivana; Muzi, Alessia; Vernole, Patrizia; Graziani, Grazia; Lococo, Emanuela; Faraldi, Martina; Maras, Bruno; Scarpa, Sigfrido; Mosca, Luciana; d'Erme, Maria

    2013-01-01

    Amyloid beta peptide (Aβ) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25–35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25–35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25–35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25–35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25–35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25–35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed. PMID:24086258

  12. Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?

    PubMed Central

    Teich, Andrew F.; Arancio, Ottavio

    2013-01-01

    The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of β-amyloid in the brain of AD patients (the ‘Amyloid Hypothesis’). Yet, many therapeutic strategies based on lowering β-amyloid have so far failed in clinical trials. This failure of β-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that β-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of β-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating β-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of β-amyloid in neuronal physiology. Another possible problem may be that toxic β-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of β-amyloid disrupt synaptic physiology. PMID:22891628

  13. Formation of Amyloid Fibers by Monomeric Light Chain Variable Domains*

    PubMed Central

    Brumshtein, Boris; Esswein, Shannon R.; Landau, Meytal; Ryan, Christopher M.; Whitelegge, Julian P.; Phillips, Martin L.; Cascio, Duilio; Sawaya, Michael R.; Eisenberg, David S.

    2014-01-01

    Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers. PMID:25138218

  14. Amyloid fibril formation by macrophage migration inhibitory factor

    SciTech Connect

    Lashuel, Hilal A. . E-mail: hilal.lashuel@epfl.ch; Aljabari, Bayan; Sigurdsson, Einar M.; Metz, Christine N.; Leng Lin; Callaway, David J.E.; Bucala, Richard

    2005-12-16

    We demonstrate herein that human macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine expressed in the brain and not previously considered to be amyloidogenic, forms amyloid fibrils similar to those derived from the disease associated amyloidogenic proteins {beta}-amyloid and {alpha}-synuclein. Acid denaturing conditions were found to readily induce MIF to undergo amyloid fibril formation. MIF aggregates to form amyloid-like structures with a morphology that is highly dependent on pH. The mechanism of MIF amyloid formation was probed by electron microscopy, turbidity, Thioflavin T binding, circular dichroism spectroscopy, and analytical ultracentrifugation. The fibrillar structures formed by MIF bind Congo red and exhibit the characteristic green birefringence under polarized light. These results are consistent with the notion that amyloid fibril formation is not an exclusive property of a select group of amyloidogenic proteins, and contribute to a better understanding of the factors which govern protein conformational changes and amyloid fibril formation in vivo.

  15. Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy.

    PubMed Central

    Li, K.; Kyle, R. A.; Dyck, P. J.

    1992-01-01

    To test whether immunohistochemical characterization of proteins in amyloid deposits in biopsied sural nerves gives reliable and useful diagnostic information using commercially available reagents, biopsy specimens of sural nerves from 38 patients with amyloid neuropathy were studied. Transthyretin (TTR) was detected in the amyloid deposits of 11 nerves, lambda light chains (LC) in 8 nerves, kappa LC in 7 nerves, and both lambda and kappa LC in 3 nerves. In 9 nerves, the amyloid deposits were too small to allow adequate immunohistochemical characterization of amyloid proteins in serial sections. Evidence that immunohistochemical characterization was correct came from: 1) evaluation of kin, 2) search for monoclonal proteins in the plasma, and 3) sequencing of the gene abnormalities in TTR+ cases. In 9 of 11 TTR+ cases, in which DNA could be obtained, sequencing of the gene showed that each of the 9 cases was heterozygous for a gene mutation; 7 had previously described mutations and 2 undescribed mutations. Therefore, in the nine sporadic cases without plasma monoclonal light chains, the immunohistochemical characterization correctly identified the protein in amyloid as transthyretin. Likewise, there was a high concordance between immunoglobulin light chains in plasma and light chains in amyloid in primary amyloidosis. Evaluation of the type, distribution, and severity of the neurologic symptoms and deficits showed: 1) the sensorimotor and autonomic neuropathy of amyloidosis characteristically affects proximal as well as distal limbs, and 2) the type of amyloidosis probably cannot be determined from the characteristics or severity of the neuropathy alone or from the location or size of amyloid deposits in nerve. Images Figure 1 PMID:1321563

  16. Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring

    PubMed Central

    Chesebro, Bruce; Race, Brent; Meade-White, Kimberly; LaCasse, Rachel; Race, Richard; Klingeborn, Mikael; Striebel, James; Dorward, David; McGovern, Gillian; Jeffrey, Martin

    2010-01-01

    Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease. PMID:20221436

  17. The amyloid precursor protein represses expression of acetylcholinesterase in neuronal cell lines.

    PubMed

    Hicks, David A; Makova, Natalia Z; Gough, Mallory; Parkin, Edward T; Nalivaeva, Natalia N; Turner, Anthony J

    2013-09-01

    The toxic role of amyloid β peptides in Alzheimer's disease is well documented. Their generation is via sequential β- and γ-secretase cleavage of the membrane-bound amyloid precursor protein (APP). Other APP metabolites include the soluble ectodomains sAPPα and sAPPβ and also the amyloid precursor protein intracellular domain (AICD). In this study, we examined whether APP is involved in the regulation of acetylcholinesterase (AChE), which is a key protein of the cholinergic system and has been shown to accelerate amyloid fibril formation and increase their toxicity. Overexpression of the neuronal specific isoform, APP695, in the neuronal cell lines SN56 and SH-SY5Y substantially decreased levels of AChE mRNA, protein, and catalytic activity. Although similar decreases in mRNA levels were observed of the proline-rich anchor of AChE, PRiMA, no changes were seen in mRNA levels of the related enzyme, butyryl-cholinesterase, nor of the high-affinity choline transporter. A γ-secretase inhibitor did not affect AChE transcript levels or enzyme activity in SN56 (APP695) or SH-SY5Y (APP695) cells, showing that regulation of AChE by APP does not require the generation of AICD or amyloid β peptide. Treatment of wild-type SN56 cells with siRNA targeting APP resulted in a significant up-regulation in AChE mRNA levels. Mutagenesis studies suggest that the observed transcriptional repression of AChE is mediated by the E1 region of APP, specifically its copper-binding domain, but not the C-terminal YENTPY motif. In conclusion, AChE is regulated in two neuronal cell lines by APP in a manner independent of the generation of sAPPα, sAPPβ, and AICD. PMID:23897820

  18. Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Yoshikura, Nobuaki; Asano, Takahiko; Hatano, Taku; Tatsumi, Shinsui; Satoh, Katsuya; Kimura, Akio; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2015-11-15

    We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT. PMID:26421831

  19. Nanoparticles and amyloid systems: A fatal encounter?

    NASA Astrophysics Data System (ADS)

    Abel, Bernd

    2014-10-01

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs thave been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

  20. Serum amyloid P inhibits dermal wound healing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  1. Bap: A New Type of Functional Amyloid.

    PubMed

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals. PMID:27451288

  2. Fibrillar Amyloid Plaque Formation Precedes Microglial Activation

    PubMed Central

    Steinbach, Sonja; Blazquez-Llorca, Lidia; Herms, Jochen

    2015-01-01

    In Alzheimer’s disease (AD), hallmark β-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9) revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 μm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9)xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo. PMID:25799372

  3. Nanoparticles and amyloid systems: A fatal encounter?

    SciTech Connect

    Abel, Bernd

    2014-10-06

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs have been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

  4. Immunoglobulin light chains, glycosaminoglycans and amyloid.

    SciTech Connect

    Stevens, F. J.; Kisilevsky, R.; Biosciences Division; Queen's Univ.

    2000-03-01

    Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as g2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the g peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normal protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue o shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans.

  5. Influence of Adsorption on Proteins and Amyloid Detection by Silicon Nitride Nanopore.

    PubMed

    Balme, Sébastien; Coulon, Pierre Eugène; Lepoitevin, Mathilde; Charlot, Benoît; Yandrapalli, Naresh; Favard, Cyril; Muriaux, Delphine; Bechelany, Mikhael; Janot, Jean-Marc

    2016-09-01

    For the past 2 decades, emerging single-nanopore technologies have opened the route to multiple sensing applications. Besides DNA sensing, the identification of proteins and amyloids is a promising field for early diagnosis. However, the influence of the interactions between the nanopore surface and proteins should be taken into account. In this work, we have selected three proteins (avidin, lysozyme, and IgG) that exhibit different affinities with the SiNx surface, and we have also examined lysozyme amyloid. Our results show that the piranha treatment of SiNx significantly decreases protein adsorption. Moreover, we have successfully detected all proteins (pore diameter 17 nm) and shown the possibility of discriminating between denatured lysozyme and its amyloid. For all proteins, the capture rates are lower than expected, and we evidence that they are correlated with the affinity of proteins to the surface. Our result confirms that proteins interacting only with the nanopore surface wall stay long enough to be detected. For lysozyme amyloid, we show that the use of the nanopore is suitable for determining the number of monomer units even if only the proteins interacting with the nanopore are detected. PMID:27506271

  6. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.

    PubMed

    Huijbers, Willem; Mormino, Elizabeth C; Schultz, Aaron P; Wigman, Sarah; Ward, Andrew M; Larvie, Mykol; Amariglio, Rebecca E; Marshall, Gad A; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A

    2015-04-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  7. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

    PubMed Central

    Mormino, Elizabeth C.; Schultz, Aaron P.; Wigman, Sarah; Ward, Andrew M.; Larvie, Mykol; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.

    2015-01-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity—consistent with findings in genetic at-risk populations—and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer’s disease continuum. Here, we examine the contribution of amyloid-β deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  8. Mechanism of soluble beta-amyloid 25-35 neurotoxicity in primary cultured rat cortical neurons.

    PubMed

    Wang, Yong; Liu, Lili; Hu, Weimin; Li, Guanglai

    2016-04-01

    This study aimed to determine the effects of different concentrations of soluble beta-amyloid 25-35 (Aβ25-35) on cell viability, calcium overload, and PI3K-p85 expression in cultured cortical rat neurons. Primary cultured cerebral cortical neurons of newborn rats were divided randomly into six groups. Five groups were treated with soluble Aβ25-35 at concentrations of 10nmol/L, 100nmol/L, 1μmol/L, 10μmol/L, or 30μmol/L. Cell Counting Kit-8 staining was used to measure cell viability, laser-scanning confocal imaging was used to detect changes in intracellular free calcium concentration, and western blot assay was used to measure neuronal PI3K-p85 expression. Soluble Aβ25-35 was found to reduce cell viability and induce calcium overload in primary cultured rat cerebral cortical neurons, in a concentration-dependent manner. At certain concentrations, soluble Aβ25-35 also increased neuronal PI3K-p85 expression. These findings reveal that soluble Aβ25-35 reduces the viability of cultured cerebral cortical rat neurons. The neurotoxicity mechanism may involve calcium overload and disruption of insulin signal transduction pathways. PMID:26940239

  9. Arterial tree asymmetry reduces cerebral pulsatility.

    PubMed

    Vrselja, Zvonimir; Brkic, Hrvoje; Curic, Goran

    2015-11-01

    With each heartbeat, pressure wave (PW) propagates from aorta toward periphery. In cerebral circulation, at the level of circle of Willis (CW), four arteries and four PWs converge. Since the interference is an elemental property of the wave, PWs interfere at the level of CW. We hypothesize that the asymmetry of brain-supplying arteries (that join to form CW) creates phase difference between the four PWs that interfere at the level of CW and reduce downstream cerebral pulsatility. To best of our knowledge, the data about the sequence of PWs' arrival into the cerebral circulation is lacking. Evident imperfect bilateral symmetry of the vessels results with different path length of brain-supplying arteries, hence, PWs should arrive into the head at different times. The probabilistic calculation shows that asynchronous arrival is more probable than synchronous. The importance of PWs for the cerebral circulation is highlighted by the observation that barotrauma protection mechanisms are more influenced by the crest of PW (pulse pressure) than by the mean arterial pressure. In addition, an increased arterial pulsatility is associated with several brain pathologies. We created simple computational models of four converging arteries and found that asynchronous arrival of the PWs results with lower maximum pressure, slower rate of pressure amplification and lower downstream pulsatility. In analogy, the asynchronous arrival of the pressure waves into the cerebral circulation should decrease blood flow pulsatility and lower transmission of kinetic energy on arterial wall. We conclude that asynchronous arrival of PWs into the cerebral circulation influences cerebral hemodynamics and represents a physiological necessity. PMID:26277658

  10. Effects of cerebral ischemia on neuronal hemoglobin

    PubMed Central

    He, Yangdong; Hua, Ya; Liu, Wenquan; Hu, Haitao; Keep, Richard F.; Xi, Guohua

    2009-01-01

    Summary The present study examined whether or not neuronal hemoglobin (Hb) is present in rats. It then examined whether cerebral ischemia or ischemic preconditioning (IPC) affects neuronal Hb levels in vivo and in vitro. In vivo, male Sprague-Dawley rats were subjected to either 15 minutes of transient middle cerebral artery occlusion with 24 hours of reperfusion, an IPC stimulus, or 24 hours of permanent middle cerebral artery occlusion (pMCAO), or IPC followed three days later by 24 hours of pMCAO. In vitro, primary cultured neurons were exposed to 2 hours of oxygen-glucose deprivation with 22 hours of reoxygenation. Results showed that Hb is widely expressed in rat cerebral neurons but not astrocytes. Hb expression was significantly upregulated in the ipsilateral caudate and the cortical core of the middle cerebral artery territory after IPC. Hb levels also increased in more penumbral cortex and the contralateral hemisphere 24 hours after pMCAO, but expression in the ipsilateral caudate and cortical core area were decreased. Ischemic preconditioning modified pMCAO-induced brain Hb changes. Neuronal Hb levels in vitro were increased by 2 hours of oxygen-glucose deprivation and 22 hours of reoxygenation. These results indicate that Hb is synthesized in neurons and can be upregulated by ischemia. PMID:19066615

  11. Rehabilitation in cerebral palsy.

    PubMed Central

    Molnar, G. E.

    1991-01-01

    Cerebral palsy is the most frequent physical disability of childhood onset. Over the past four decades, prevalence has remained remarkably constant at 2 to 3 per 1,000 live births in industrialized countries. In this article I concentrate on the rehabilitation and outcome of patients with cerebral palsy. The epidemiologic, pathogenetic, and diagnostic aspects are highlighted briefly as they pertain to the planning and implementation of the rehabilitation process. PMID:1866952

  12. Nanomedicine in cerebral palsy

    PubMed Central

    Balakrishnan, Bindu; Nance, Elizabeth; Johnston, Michael V; Kannan, Rangaramanujam; Kannan, Sujatha

    2013-01-01

    Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed. PMID:24204146

  13. Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

    PubMed Central

    Anoop, Arunagiri; Ranganathan, Srivastav; Dhaked, Bhagwan Das; Jha, Narendra Nath; Pratihar, Supriya; Ghosh, Saikat; Sahay, Shruti; Kumar, Santosh; Das, Subhadeep; Kombrabail, Mamata; Agarwal, Kumud; Jacob, Reeba S.; Singru, Praful; Bhaumik, Prasenjit; Padinhateeri, Ranjith; Kumar, Ashutosh; Maji, Samir K.

    2014-01-01

    The storage of protein/peptide hormones within subcellular compartments and subsequent release are crucial for their native function, and hence these processes are intricately regulated in mammalian systems. Several peptide hormones were recently suggested to be stored as amyloids within endocrine secretory granules. This leads to an apparent paradox where storage requires formation of aggregates, and their function requires a supply of non-aggregated peptides on demand. The precise mechanism behind amyloid formation by these hormones and their subsequent release remain an open question. To address this, we examined aggregation and fibril reversibility of a cyclic peptide hormone somatostatin (SST)-14 using various techniques. After proving that SST gets stored as amyloid in vivo, we investigated the role of native structure in modulating its conformational dynamics and self-association by disrupting the disulfide bridge (Cys3–Cys14) in SST. Using two-dimensional NMR, we resolved the initial structure of somatostatin-14 leading to aggregation and further probed its conformational dynamics in silico. The perturbation in native structure (S-S cleavage) led to a significant increase in conformational flexibility and resulted in rapid amyloid formation. The fibrils formed by disulfide-reduced noncyclic SST possess greater resistance to denaturing conditions with decreased monomer releasing potency. MD simulations reveal marked differences in the intermolecular interactions in SST and noncyclic SST providing plausible explanation for differential aggregation and fibril reversibility observed experimentally in these structural variants. Our findings thus emphasize that subtle changes in the native structure of peptide hormone(s) could alter its conformational dynamics and amyloid formation, which might have significant implications on their reversible storage and secretion. PMID:24782311

  14. Development and characterization of a TAPIR-like mouse monoclonal antibody to amyloid-beta.

    PubMed

    Wang, Jun; Hara, Hideo; Makifuchi, Takao; Tabira, Takeshi

    2008-06-01

    Tissue amyloid plaque immuno-reactive (TAPIR) antibody was better related to the effect of immunotherapy in Alzheimer's disease (AD) than ELISA antibody. Here we used a hybridoma technique to develop a TAPIR-like anti-human amyloid-beta (Abeta) mouse monoclonal antibody. The obtained monoclonal antibody, 3.4A10, was an IgG2b isotype and recognized N-terminal portion of Abeta1-42 without binding denatured or native amyloid-beta protein precursor. It had higher affinity to Abeta1-42 than to Abeta1-40 by Biacore affinity analysis and stained preferably the peripheral part of senile plaques and recognized the plaque core less than 4G8. It inhibited the Abeta1-42 fibril formation as well as degraded pre-aggregated Abeta1-42 peptide in a thioflavin T fluorescence spectrophotometry assay. The in vivo studies showed that 3.4A10 treatment decreased amyloid burden compared to the control group and significantly reduced Abeta42 levels rather than Abeta40 levels in brain lysates as well as the Abeta*56 oligomer (12mer) in TBS fraction of the brain lysates. 3.4A10 entered brain and decorated some plaques, which is surrounded by more Iba1-positive microglia. 3.4A10 therapy did not induce lymphocytic infiltration and obvious increase in microhemorrhage. We conclude that 3.4A10 is a TAPIR-like anti-human amyloid monoclonal antibody, and has a potential of therapeutic application for AD. PMID:18560128

  15. Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden.

    PubMed

    Yotter, Rachel A; Doshi, Jimit; Clark, Vanessa; Sojkova, Jitka; Zhou, Yun; Wong, Dean F; Ferrucci, Luigi; Resnick, Susan M; Davatzikos, Christos

    2013-12-01

    The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue ((11)C-PiB) positron emission tomography data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allowed us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression--here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance, and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, the use of which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications. PMID:23859610

  16. A Cultivated Form of a Red Seaweed (Chondrus crispus), Suppresses β-Amyloid-Induced Paralysis in Caenorhabditis elegans.

    PubMed

    Sangha, Jatinder Singh; Wally, Owen; Banskota, Arjun H; Stefanova, Roumiana; Hafting, Jeff T; Critchley, Alan T; Prithiviraj, Balakrishnan

    2015-10-01

    We report here the protective effects of a methanol extract from a cultivated strain of the red seaweed, Chondrus crispus, against β-amyloid-induced toxicity, in a transgenic Caenorhabditis elegans, expressing human Aβ1-42 gene. The methanol extract of C. crispus (CCE), delayed β-amyloid-induced paralysis, whereas the water extract (CCW) was not effective. The CCE treatment did not affect the transcript abundance of amy1; however, Western blot analysis revealed a significant decrease of Aβ species, as compared to untreated worms. The transcript abundance of stress response genes; sod3, hsp16.2 and skn1 increased in CCE-treated worms. Bioassay guided fractionation of the CCE yielded a fraction enriched in monogalactosyl diacylglycerols (MGDG) that significantly delayed the onset of β-amyloid-induced paralysis. Taken together, these results suggested that the cultivated strain of C. crispus, whilst providing dietary nutritional value, may also have significant protective effects against β-amyloid-induced toxicity in C. elegans, partly through reduced β-amyloid species, up-regulation of stress induced genes and reduced accumulation of reactive oxygen species (ROS). PMID:26492254

  17. Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice.

    PubMed

    Jacobsen, Helmut; Ozmen, Laurence; Caruso, Antonello; Narquizian, Robert; Hilpert, Hans; Jacobsen, Bjoern; Terwel, Dick; Tanghe, An; Bohrmann, Bernd

    2014-08-27

    Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance. PMID:25164658

  18. Combined Treatment with a BACE Inhibitor and Anti-Aβ Antibody Gantenerumab Enhances Amyloid Reduction in APPLondon Mice

    PubMed Central

    Ozmen, Laurence; Caruso, Antonello; Narquizian, Robert; Hilpert, Hans; Jacobsen, Bjoern; Terwel, Dick; Tanghe, An

    2014-01-01

    Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer‘s disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance. PMID:25164658

  19. A Cultivated Form of a Red Seaweed (Chondrus crispus), Suppresses β-Amyloid-Induced Paralysis in Caenorhabditis elegans

    PubMed Central

    Sangha, Jatinder Singh; Wally, Owen; Banskota, Arjun H.; Stefanova, Roumiana; Hafting, Jeff T.; Critchley, Alan T.; Prithiviraj, Balakrishnan

    2015-01-01

    We report here the protective effects of a methanol extract from a cultivated strain of the red seaweed, Chondrus crispus, against β-amyloid-induced toxicity, in a transgenic Caenorhabditis elegans, expressing human Aβ1-42 gene. The methanol extract of C. crispus (CCE), delayed β-amyloid-induced paralysis, whereas the water extract (CCW) was not effective. The CCE treatment did not affect the transcript abundance of amy1; however, Western blot analysis revealed a significant decrease of Aβ species, as compared to untreated worms. The transcript abundance of stress response genes; sod3, hsp16.2 and skn1 increased in CCE-treated worms. Bioassay guided fractionation of the CCE yielded a fraction enriched in monogalactosyl diacylglycerols (MGDG) that significantly delayed the onset of β-amyloid-induced paralysis. Taken together, these results suggested that the cultivated strain of C. crispus, whilst providing dietary nutritional value, may also have significant protective effects against β-amyloid-induced toxicity in C. elegans, partly through reduced β-amyloid species, up-regulation of stress induced genes and reduced accumulation of reactive oxygen species (ROS). PMID:26492254

  20. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

    PubMed Central

    Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

    2016-01-01

    Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

  1. Relative impact of amyloid-β, lacunes, and downstream imaging markers on cognitive trajectories.

    PubMed

    Kim, Hee Jin; Yang, Jin Ju; Kwon, Hunki; Kim, Changsoo; Lee, Jong Min; Chun, Phillip; Kim, Yeo Jin; Jung, Na-Yeon; Chin, Juhee; Kim, Seonwoo; Woo, Sook-Young; Choe, Yearn Seong; Lee, Kyung-Han; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Weiner, Michael W; Na, Duk L; Seo, Sang Won

    2016-09-01

    SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal

  2. Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein.

    PubMed

    Urani, Alexandre; Romieu, Pascal; Roman, François J; Yamada, Kiyofumi; Noda, Yukihiro; Kamei, Hiroyuki; Manh Tran, Hung; Nagai, Taku; Nabeshima, Toshitaka; Maurice, Tangui

    2004-02-20

    Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms. PMID:14975704

  3. Cerebral Small Vessel Disease and Arterial Stiffness: Tsunami Effect in the Brain?

    PubMed Central

    Saji, Naoki; Toba, Kenji; Sakurai, Takashi

    2016-01-01

    Background Cerebral small vessel diseases, including silent lacunar infarcts, white matter hyperintensities, and microbleeds, pose a risk for cerebrovascular disease, cognitive impairment, and the geriatric syndrome via effects on arterial stiffness. However, the vascular, physiological, and metabolic roles of arterial stiffness in cerebral small vessel diseases remain unclear. Summary Arterial stiffness can be assessed using various indicators such as the ankle-brachial index, pulse wave velocity, cardio-ankle vascular index, and augmentation index. Arterial stiffness is independently associated with all components of cerebral small vessel disease including silent lacunar infarcts, white matter hyperintensities, and microbleeds, although there are some methodological differences between the various surrogate markers. Evidence of arterial stiffness indicates microvessel arteriosclerosis presenting with vascular endothelial dysfunction. Further, vascular narrowing due to atherosclerosis and vascular stiffness due to lipohyalinosis can accelerate the pulse waves. This hemodynamic stress, pulsatile pressure, or blood pressure variability can cause a ‘tsunami effect’ towards the cerebral parenchyma and lead to cerebral small vessel disease. Previous studies have shown that silent lacunar infarcts and white matter hyperintensities are strongly associated with arterial stiffness. However, the association between microbleeds and arterial stiffness remains controversial, as there are two vessel mechanisms related to microbleeds: cerebral amyloid angiopathy and hypertensive small vessel disease. Key Messages Cerebral small vessel disease with associated arterial stiffness is a risk factor for silent cerebral lesions, stroke, and cognitive impairment. Improvement of the living environment, management of risk factors, and innovation and development of novel drugs that improve arterial stiffness may suppress the progression of cerebral small vessel disease, and may reduce

  4. Amyloid persistence in decellularized liver: biochemical and histopathological characterization

    PubMed Central

    Mazza, Giuseppe; Simons, J. Paul; Al-Shawi, Raya; Ellmerich, Stephan; Urbani, Luca; Giorgetti, Sofia; Taylor, Graham W.; Gilbertson, Janet A.; Hall, Andrew R.; Al-Akkad, Walid; Dhar, Dipok; Hawkins, Philip N.; De Coppi, Paolo; Pinzani, Massimo; Bellotti, Vittorio; Mangione, P. Patrizia

    2016-01-01

    Abstract Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity. PMID:26646718

  5. Direct observation of amyloid nucleation under nanomechanical stretching

    NASA Astrophysics Data System (ADS)

    Varongchayakul, Nitinun

    Self-assembly of amyloid nanofiber is associated with functional and pathological processes such as in neurodegenerative diseases. Despite intensive studies, stochastic nature of the process has made it difficult to elucidate molecular mechanisms for the key amyloid nucleation. Here, we investigated the amyloid nucleation of silk-elastin-like peptide (SELP) using time-lapse lateral force microscopy (LFM). By repeated scanning a single line on a SELP-coated mica surface, we observed sudden stepwise height increases, corresponds to nucleation of an amyloid fiber. The lateral force profiles followed either a worm-like chain model or an exponential function, suggesting that the atomic force microscopy (AFM) tip stretches a single or multiple SELP molecules along the scanning direction, serves as the template for further self-assembly perpendicular to the scan direction. Such mechanically induced nucleation of amyloid fibrils allows positional and directional control of amyloid assembly in vitro , which we demonstrate by generating single nanofibers at predetermined nucleation sites.

  6. Molecular basis for amyloid fibril formation and stability

    PubMed Central

    Makin, O. Sumner; Atkins, Edward; Sikorski, Pawel; Johansson, Jan; Serpell, Louise C.

    2005-01-01

    The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel β-sheets in a cross-β arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel β-sheets are zipped together by means of π-bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid–lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils. PMID:15630094

  7. Size Effect of Graphene Oxide on Modulating Amyloid Peptide Assembly.

    PubMed

    Wang, Jie; Cao, Yunpeng; Li, Qiang; Liu, Lei; Dong, Mingdong

    2015-06-26

    Protein misfolding and abnormal assembly could lead to aggregates such as oligomer, proto-fibril, mature fibril, and senior amyloid plaques, which are associated with the pathogenesis of many amyloid diseases. These irreversible amyloid aggregates typically form in vivo and researchers have been endeavoring to find new modulators to invert the aggregation propensity in vitro, which could increase understanding in the mechanism of the aggregation of amyloid protein and pave the way to potential clinical treatment. Graphene oxide (GO) was shown to be a good modulator, which could strongly control the amyloidosis of Aβ (33-42). In particular, quartz crystal microbalance (QCM), circular dichroism (CD) spectroscopy, and atomic force microscopy (AFM) measurements revealed the size-dependent manner of GO on modulating the assembly of amyloid peptides, which could be a possible way to regulate the self-assembled nanostructure of amyloid peptide in a predictable manner. PMID:26031933

  8. Atomic View of a Toxic Amyloid Small Oligomer

    SciTech Connect

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  9. Amyloid persistence in decellularized liver: biochemical and histopathological characterization.

    PubMed

    Mazza, Giuseppe; Simons, J Paul; Al-Shawi, Raya; Ellmerich, Stephan; Urbani, Luca; Giorgetti, Sofia; Taylor, Graham W; Gilbertson, Janet A; Hall, Andrew R; Al-Akkad, Walid; Dhar, Dipok; Hawkins, Philip N; De Coppi, Paolo; Pinzani, Massimo; Bellotti, Vittorio; Mangione, P Patrizia

    2016-01-01

    Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity. PMID:26646718

  10. Structural requirements of glycosaminoglycans for facilitating amyloid fibril formation of human serum amyloid A.

    PubMed

    Takase, Hiroka; Tanaka, Masafumi; Yamamoto, Aki; Watanabe, Shiori; Takahashi, Sanae; Nadanaka, Satomi; Kitagawa, Hiroshi; Yamada, Toshiyuki; Mukai, Takahiro

    2016-06-01

    Serum amyloid A (SAA) is a precursor protein of amyloid fibrils. Given that heparan sulfate (HS), a glycosaminoglycan (GAG), is detected in amyloid deposits, it has been suggested that GAG is a key component of amyloid fibril formation. We previously reported that heparin (an analog of HS) facilitates the fibril formation of SAA, but the structural requirements remain unknown. In the present study, we investigated the structural requirements of GAGs for facilitating the amyloid fibril formation of SAA. Spectroscopic analyses using structurally diverse GAG analogs suggested that the fibril formation of SAA was facilitated irrespective of the backbone structure of GAGs; however, the facilitating effect was strongly correlated with the degree of sulfation. Microscopic analyses revealed that the morphologies of SAA aggregates were modulated by the GAGs. The HS molecule, which is less sulfated than heparin but contains highly sulfated domains, exhibited a relatively high potential to facilitate fibril formation compared to other GAGs. The length dependence of fragmented heparins on the facilitating effect suggested that a high density of sulfate groups is also required. These results indicate that not only the degree of sulfation but also the lengths of sulfated domains in GAG play important roles in fibril formation of SAA. PMID:27097047

  11. Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia.

    PubMed

    Chi, O Z; Barsoum, S; Vega-Cotto, N M; Jacinto, E; Liu, X; Mellender, S J; Weiss, H R

    2016-03-01

    Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5±0.8% control vs. 21.5±0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion. PMID:26742793

  12. EFFECTS OF RAPAMYCIN ON CEREBRAL OXYGEN SUPPLY AND CONSUMPTION DURING REPERFUSION AFTER CEREBRAL ISCHEMIA

    PubMed Central

    CHI, O. Z.; BARSOUM, S.; VEGA-COTTO, N. M.; JACINTO, E.; LIU, X.; MELLENDER, S. J.; WEISS, H. R.

    2016-01-01

    Abstract—Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia–reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with and without rapamycin (20 mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5 ± 0.8% control vs. 21.5 ± 0.9% rapamycin). We also found that ischemia–reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia–reperfusion. PMID:26742793

  13. Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice.

    PubMed

    Zhang, Zui; Ohtake-Niimi, Shiori; Kadomatsu, Kenji; Uchimura, Kenji

    2016-08-01

    Alzheimer's disease (AD) is a progressive disorder leading to cognitive impairment and neuronal loss. Cerebral extracellular accumulation and deposition of amyloid ß plaques is a pathological hallmark of AD. Chondroitin sulfate (CS) is an extracellular component abundant in the brain. CS is a sulfated glycosaminoglycan covalently attached to a core protein, forming chondroitin sulfate proteoglycan. The structure of CS is heterogeneous with sulfation modification and elongation of the chain. The structural diversity of CS allows it to play various roles in the brain. Increasing evidence has shown that CS promotes aggregation of amyloid ß peptides into higher-order species such as insoluble amyloid ß fibrils. Difficulties in the structural analysis of brain CS, as well as its heterogeneity, limit the study of potential roles of CS in AD pathology. Here we established a microanalysis method with reversed-phase ion-pair high performance liquid chromatography and found that CS in the brains of Tg2576 AD model mice show a lower molecular size and an increased ratio of CS-B motif di-sulfated disaccharide. Our findings provide insight into the structural changes of cerebral CS upon Alzheimer's pathogenesis. PMID:27578913

  14. In Alzheimer's disease, hypometabolism in low-amyloid brain regions may be a functional consequence of pathologies in connected brain regions.

    PubMed

    Klupp, Elisabeth; Förster, Stefan; Grimmer, Timo; Tahmasian, Masoud; Yakushev, Igor; Sorg, Christian; Yousefi, Behrooz H; Drzezga, Alexander

    2014-06-01

    In patients with Alzheimer's disease (AD), prominent hypometabolism has been observed in brain regions with minor amyloid load. These hypometabolism-only (HO) areas cannot be explained merely as a consequence of local amyloid toxicity. The aim of this multimodal imaging study was to explore whether such HO phenomenon may be related to pathologies in functionally connected, remote brain regions. Nineteen AD patients and 15 matched controls underwent examinations with [(11)C]PiB-PET and [(18)F]FDG-PET. Voxel-based statistical group comparisons were performed to obtain maps of significantly elevated amyloid burden and reduced cerebral glucose metabolism, respectively, in patients. An HO area was identified by subtraction of equally thresholded result maps (hypometabolism minus amyloid burden). To identify the network typically functionally connected to this HO area, it was used as a seed region for a functional connectivity analysis in resting-state functional magnetic resonance imaging data of 17 elderly healthy controls. The resulting intrinsic connectivity network (HO-ICN) was retransferred into the brains of AD patients to be able to analyze pathologies within this network in the positron emission tomography (PET) datasets. The most prominent HO area was detected in the left middle frontal gyrus of AD patients. The HO-ICN in healthy controls showed a major overlap with brain areas significantly affected by both amyloid deposition and hypometabolism in patients. This association was substantiated by the results of region-of-interest-based and voxel-wise correlation analyses, which revealed strong correlations between the degree of hypometabolism within the HO region and within the HO-ICN. These results support the notion that hypometabolism in brain regions not strongly affected by locoregional amyloid pathology may be related to ongoing pathologies in remote but functionally connected regions, that is, by reduced neuronal input from these regions. PMID:24870443

  15. Evidence for Novel [beta]-Sheet Structures in Iowa Mutant [beta]-Amyloid Fibrils

    SciTech Connect

    Tycko, Robert; Sciarretta, Kimberly L.; Orgel, Joseph P.R.O.; Meredith, Stephen C.

    2009-07-24

    Asp23-to-Asn mutation within the coding sequence of {beta}-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-A{beta}40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-A{beta}40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10{sup -3} min{sup -1} and 1.07 x 10{sup -4} min{sup -1} for D23N-A{beta}40 and the wild-type peptide WT-A{beta}40, respectively) and without a lag phase. Electron microscopy shows that D23N-A{beta}40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-{beta} pattern, with a sharp reflection at 4.7 {angstrom} and a broad reflection at 9.4 {angstrom}, which is notably smaller than the value for WT-A{beta}40 fibrils (10.4 {angstrom}). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-A{beta}40 fibrils containing the in-register, parallel {beta}-sheet structure commonly found in WT-A{beta}40 fibrils and most other amyloid fibrils. Antiparallel {beta}-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through 13C-13C and 15N-13C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-A{beta}40 fibrils and the unusual vasculotropic clinical picture in these patients.

  16. Amyloid β peptide stimulates platelet activation through RhoA-dependent modulation of actomyosin organization.

    PubMed

    Sonkar, Vijay K; Kulkarni, Paresh P; Dash, Debabrata

    2014-04-01

    Platelets contribute to 95% of circulating amyloid precursor protein in the body and have widely been employed as a "peripheral" model of neurons in Alzheimer's disease. We sought to analyze the effects of amyloid β (Aβ) on platelets and to understand the underlying molecular mechanism. The Aβ active fragment containing amino acid sequence 25-35 (Aβ(25-35); 10-20 μM) was found to induce strong aggregation of human platelets, granule release, and integrin activation, similar to that elicited by physiological agonists. Platelets exposed to Aβ(25-35) retracted fibrin clot and displayed augmented adhesion to collagen under arterial shear, reflective of a switch to prothrombotic phenotype. Exposure of platelets to Aβ peptide (20 μM) resulted in a 4.2- and 2.3-fold increase in phosphorylation of myosin light chain (MLC) and MLC phosphatase, respectively, which was reversed by Y27632, an inhibitor of Rho-associated coiled-coil protein kinase (ROCK). Aβ(25-35)-induced platelet aggregation and clot retraction were also significantly attenuated by Y27632. Consistent with these findings, Aβ(25-35) elicited a significant rise in the level of RhoA-GTP in platelets. Platelets pretreated with reverse-sequenced Aβ fragment (Aβ(35-25)) and untreated resting platelets served as controls. We conclude that Aβ induces cellular activation through RhoA-dependent modulation of actomyosin, and hence, RhoA could be a potential therapeutic target in Alzheimer's disease and cerebral amyloid angiopathy. PMID:24421399

  17. Amyloids, Melanins and Oxidative Stress in Melanomagenesis

    PubMed Central

    Liu-Smith, Feng; Poe, Carrie; Farmer, Patrick J.; Meyskens, Frank L.

    2015-01-01

    Melanoma has traditionally been viewed as an ultra-violet (UV) radiation induced malignancy. While UV is a common inducing factor, other endogenous stresses such as metal ion accumulation or the melanin pigment itself, may provide alternative pathways to melanoma progression. Eumelanosomes within melanoma often exhibit disrupted membranes and fragmented pigment which may be due to alterations in their amyloid-based striatial matrix. The melanosomal amyloid can itself be toxic, especially in combination with reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by endogenous NADPH oxidase (NOX) and nitric oxide synthase (NOS) enzymes; a toxic mix that may initiate melanomagenesis. Further understanding of the loss of the melanosomal organization, the behavior of the exposed melanin, and the induction of ROS/RNS in melanomas may provide critical insights into this deadly disease. PMID:25271672

  18. Stability and cytotoxicity of crystallin amyloid nanofibrils.

    PubMed

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J; Valery, Celine; Gerrard, Juliet A; Sasso, Luigi

    2014-11-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. PMID:25255060

  19. General anesthetics and β-amyloid protein.

    PubMed

    Xie, Zhongcong; Xu, Zhipeng

    2013-12-01

    With roughly 234 million people undergoing surgery with anesthesia each year worldwide, it is important to determine whether commonly used anesthetics can induce any neurotoxicity. Alzheimer's disease (AD) is the most common form of age-related dementia, and a rapidly growing health problem. Several studies suggest that anesthesia could be associated with the development of AD. Moreover, studies in cultured cells and animals show that commonly used inhalation anesthetics may induce changes consistent with AD neuropathogenesis, e.g., β-amyloid protein accumulation. Therefore, in this mini review, we focus on the recent research investigating the effects of commonly used anesthetics including isoflurane, sevoflurane, desflurane, nitrous oxide, and propofol, on Aβ accumulation in vitro and in vivo. We further discuss the future direction of the research determining the effects of anesthetics on β-amyloid protein accumulation. PMID:22918033

  20. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.

    PubMed

    Ferretti, M T; Merlini, M; Späni, C; Gericke, C; Schweizer, N; Enzmann, G; Engelhardt, B; Kulic, L; Suter, T; Nitsch, R M

    2016-05-01

    Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease. PMID:26872418

  1. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.

    PubMed

    Rosen, Rebecca F; Tomidokoro, Yasushi; Farberg, Aaron S; Dooyema, Jeromy; Ciliax, Brian; Preuss, Todd M; Neubert, Thomas A; Ghiso, Jorge A; LeVine, Harry; Walker, Lary C

    2016-08-01

    The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. PMID:27318146

  2. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  3. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    PubMed

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  4. X-ray crystal structure of the protease inhibitor domain of Alzheimer's amyloid. beta. -protein precursor

    SciTech Connect

    Hynes, T.R.; Randal, M.; Kennedy, L.A.; Eigenbrot, C.; Kossiakoff, A.A. Univ. of California, San Francisco )

    1990-10-01

    Alzheimer's amyloid {beta}-protein precursor contains a Kunitz protease inhibitor domain (APPI) potentially involved in proteolytic events leading to cerebral amyloid deposition. To facilitate the identification of the physiological target of the inhibitor, the crystal structure of APPI has been determined and refined to 1.5-{Angstrom} resolution. Sequences in the inhibitor-protease interface of the correct protease target will reflect the molecular details of the APPI structure. While the overall tertiary fold of APPI is very similar to that of the Kunitz inhibitor BPTI, a significant rearrangement occurs in the backbone conformation of one of the two protease binding loops. A number of Kunitz inhibitors have similar loop sequences, indicating the structural alteration is conserved and potentially an important determinant of inhibitor specificity. In a separate region of the protease binding loops, APPI side chains Met-17 and Phe-34 create an exposed hydrophobic surface in place of Arg-17 and Val-34 in BPTI. The restriction this change places on protease target sequences is seen when the structure of APPI is superimposed on BPTI complexed to serine proteases, where the hydrophobic surface of APPI faces a complementary group of nonpolar side chains on kallikrein A versus polar side chains on trypsin.

  5. Beta-secretase-cleaved amyloid precursor protein in Alzheimer brain: a morphologic study.

    PubMed

    Sennvik, Kristina; Bogdanovic, N; Volkmann, Inga; Fastbom, J; Benedikz, E

    2004-01-01

    beta-amyloid (Abeta) is the main constituent of senile plaques seen in Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP) via proteolytic cleavage by proteases beta- and gamma-secretase. In this study, we examined content and localization of beta-secretase-cleaved APP (beta-sAPP) in brain tissue sections from the frontal, temporal and occipital lobe. Strong granular beta-sAPP staining was found throughout the gray matter of all three areas, while white matter staining was considerably weaker. beta-sAPP was found to be localized in astrocytes and in axons. We found the beta-sAPP immunostaining to be stronger and more extensive in gray matter in Alzheimer disease (AD) cases than controls. The axonal beta-sAPP staining was patchy and unevenly distributed for the AD cases, indicating impaired axonal transport. beta-sAPP was also found surrounding senile plaques and cerebral blood vessels. The results presented here show altered beta-sAPP staining in the AD brain, suggestive of abnormal processing and transport of APP. PMID:15090268

  6. Cerebral tissue oxygenation impairment during experimental cerebral malaria

    PubMed Central

    Cabrales, Pedro; Martins, Yuri C; Ong, Peng Kai; Zanini, Graziela M; Frangos, John A; Carvalho, Leonardo JM

    2013-01-01

    Ischemia and hypoxia have been implicated in