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Sample records for alpha tau k5

  1. The Atmospheric Dynamics of Alpha Tau (K5 III) -- Clues to Understanding the Magnetic Dynamo

    NASA Technical Reports Server (NTRS)

    Carpenter Kenneth G.

    2008-01-01

    Using HST/GHRS, HST/STIS and FUSE archival data for (alpha) Tau and the CHIANTI spectroscopic code, we have derived line shifts, volumetric emission measures, and plasma density estimates, and calculated filling factors for a number of UV lines forming between 10,000 K and 300,000 K in the outer atmosphere of this red giant star. The data suggest the presence of low-temperature extended regions and high-temperature compact regions, associated with magnetically open and closed structures in the stellar atmosphere, respectively. The signatures of UV lines from Alpha Tau can be consistently understood via a model of upward-traveling Alfven waves in a gravitationally stratified atmosphere. These wakes cause non-thermal broadening in UV lines due to unresolved wave motions and downward plasma motions in compact magnetic loops heated by resonant .4lf\\en wave heating. We discuss implications of this interpretation for understanding the nature of magnetic dynamos operating in late-type giants.

  2. The Atmospheric Dynamics of alpha Tau (K5 III) - Clues to Understanding the Magnetic Dynamo in Late-Type Giant Stars

    NASA Technical Reports Server (NTRS)

    Carpenter, Kenneth G.; Airapetian, Vladimir

    2008-01-01

    Using HST/GHRS, HST/STIS and FUSE archival data for alpha Tau and the CHIANTI spectroscopic code, we have derived line shifts, volumetric emission measures, and plasma density estimates, and calculated filling factors for a number of UV lines forming between 10,000 K and 300,000 K in the outer atmosphere of this red giant star. The data suggest the presence of low-temperature extended regions and high-temperature compact regions, associated with magnetically open and closed structures in the stellar atmosphere, respectively. The signatures of UV lines from alpha Tau can be consistently understood via a model of upward-traveling Alfven waves in a gravitationally stratified atmosphere. These waves cause non-thermal broadening in UV lines due to unresolved wave motions and downward plasma motions in compact magnetic loops heated by resonant Alfven wave heating.

  3. The Atmospheric Dynamics of Alpha Tau (K5 III) - Clues to Understanding the Magnetic Dynamo in Late-Type Giant Stars

    NASA Technical Reports Server (NTRS)

    Carpenter, Kenneth G.; Airapetian, Vladimir

    2008-01-01

    Using HST/GHRS, HST/STIS and FUSE archival data for a Tau and the CHIANTI spectroscopic code, we have derived line shifts, volumetric emission measures, and plasma density estimates, and calculated filling factors for a number of UV lines forming between 10,000 K and 300,000 K in the outer atmosphere of this red giant star. The data suggest the presence of low-temperature extended regions and high-temperature compact regions, associated with magnetically open and closed structures in the stellar atmosphere, respectively. The signatures of UV lines from a Tau can be consistently understood via a model of upward-traveling Alfv6n waves in a gravitationally stratified atmosphere. These waves cause nonthermal broadening in UV lines due to unresolved wave motions and downward plasma motions in compact magnetic loops heated by resonant Alfven wave heating.

  4. Chromospheric heating by acoustic shocks - A confrontation of GHRS observations of Alpha Tauri (K5 III) with ab initio calculations

    NASA Technical Reports Server (NTRS)

    Judge, P. G.; Cuntz, M.

    1993-01-01

    We compare ab initio calculations of semiforbidden C II line profiles near 2325 A with recently published observations of the inactive red giant Alpha Tau (K5 III) obtained using the GHRS on board the Hubble Space Telescope. Our one-dimensional, time-dependent calculations assume that the chromosphere is heated by stochastic acoustic shocks generated by photospheric convection. We calculate various models using results from traditional (mixing length) convection zone calculations as input to hydrodynamical models. The semiforbidden C II line profiles and ratios provide sensitive diagnostics of chromospheric velocity fields, electron densities, and temperatures. We identify major differences between observed and computed line profiles which are related to basic gas dynamics and which are probably not due to technical modeling restrictions. If the GHRS observations are representative of chromospheric conditions at all epochs, then one (or more) of our model assumptions must be incorrect. Several possibilities are examined. We predict time variability of semiforbidden C II lines for comparison with observations. Based upon data from the IUE archives, we argue that photospheric motions associated with supergranulation or global pulsation modes are unimportant in heating the chromosphere of Alpha Tau.

  5. Far-Infrared and Millimeter Continuum Studies of K-Giants: Alpha Boo and Alpha Tau

    NASA Technical Reports Server (NTRS)

    Cohen, Martin; Carbon, Duane F.; Welch, William J.; Lim, Tanya; Forster, James R.; Goorvitch, David; Thigpen, William (Technical Monitor)

    2002-01-01

    We have imaged two normal, non-coronal, infrared-bright K-giants, alpha Boo and alpha Tau, in the 1.4-millimeter and 2.8-millimeter continuum using BIMA. These stars have been used as important absolute calibrators for several infrared satellites. Our goals are: (1) to probe the structure of their upper photospheres; (2) to establish whether these stars radiate as simple photospheres or possess long-wavelength chromospheres; and (3) to make a connection between millimeter-wave and far-infrared absolute flux calibrations. To accomplish these goals we also present ISO Long Wavelength Spectrometer (LWS) measurements of both these K-giants. The far-infrared and millimeter continuum radiation is produced in the vicinity of the temperature minimum in a Boo and a Tau, offering a direct test of the model photospheres and chromospheres for these two cool giants. We find that current photospheric models predict fluxes in reasonable agreement with those observed for those wavelengths which sample the upper photosphere, namely less than or equal to 170 micrometers in alpha Tau and less than or equal to 125 micrometers in alpha Boo. It is possible that alpha Tau is still radiative as far as 0.9 - 1.4 millimeters. We detect chromospheric radiation from both stars by 2.8 millimeters (by 1.4 millimeters in alpha Boo), and are able to establish useful bounds on the location of the temperature minimum. An attempt to interpret the chromospheric fluxes using the two-component "bifurcation model" proposed by Wiedemann et al. (1994) appears to lead to a significant contradiction.

  6. Short-Term Chromospheric Variability in alpha Tauri (K5 III): Results from IUE Time Series Observations

    NASA Technical Reports Server (NTRS)

    Cuntz, Manfred; Deeney, Bryan D.; Brown, Alexander; Stencel, Robert E.

    1996-01-01

    We evaluate time series observations of chromospheric lines (Mg II, Mg I, and C II) for the K giant alpha Tau obtained using the IUE LWP camera at high dispersion. These observations cover a time span of about 2 weeks in 1994 February-March and were designed to resolve variations occurring within hours, days, and weeks. We consider the observational results in relation to theoretical acoustic heating models, motivated by the fact that alpha Tau may exhibit a basal (i.e., minimum) level of chromospheric activity. The data reveal flux variations between the extremes of 8% in Mg II h+k and 15% in each emission component. These variations occur on timescales as short as 8 hr but not on timescales longer than approx.3 days. For the h and k components, flux variations occurring on a timescale as short as 1.5 hr are also found. These changes are often not correlated (and are sometimes even anticorrelated), leading to remarkable differences in the h/k ratios. We argue that these results are consistent with the presence of strong acoustic shocks, which can lead to variable Mg II line emission when only a small number of strong shocks are propagating through the atmosphere. We deduce the electron density in the C II lambda 2325 line formation region to be log(base e) of N. approx. equals 9.0, in agreement with previous studies. Our data provide evidence that the Mg II basal flux limit for K giants might be a factor of 4 higher than suggested by Rutten et al.

  7. On the Behavior of the Effective QCD Coupling {alpha}{sub {tau}}(s)at Low Scales

    SciTech Connect

    Brodsky, Stanley J.

    2002-12-11

    The hadronic decays of the {tau} lepton can be used to determine the effective charge {alpha}{tau}(m{sub {tau}{prime}}{sup 2}) for a hypothetical {tau}-lepton with mass in the range 0 < m{sub {tau}{prime}} < m{sub {tau}}. This definition provides a fundamental definition of the QCD coupling at low mass scales. We study the behavior of {alpha}{sub {tau}} at low mass scales directly from first principles and without any renormalization-scheme dependence by looking at the experimental data from the OPAL Collaboration. The results are consistent with the freezing of the physical coupling at mass scales s = m{sub {tau}{prime}}{sup 2} of order 1 GeV{sup 2} with a magnitude {alpha}{sub {tau}} {approx} 0.9 {+-} 0.1.

  8. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau

    PubMed Central

    Rousseaux, Maxime WC; de Haro, Maria; Lasagna-Reeves, Cristian A; De Maio, Antonia; Park, Jeehye; Jafar-Nejad, Paymaan; Al-Ramahi, Ismael; Sharma, Ajay; See, Lauren; Lu, Nan; Vilanova-Velez, Luis; Klisch, Tiemo J; Westbrook, Thomas F; Troncoso, Juan C; Botas, Juan; Zoghbi, Huda Y

    2016-01-01

    Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points. DOI: http://dx.doi.org/10.7554/eLife.19809.001 PMID:27779468

  9. Estrogen dissociates Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit in postischemic hippocampus.

    PubMed

    Cardona-Gómez, Gloria Patricia; Arango-Davila, Cesar; Gallego-Gómez, Juan Carlos; Barrera-Ocampo, Alvaro; Pimienta, Hernan; Garcia-Segura, Luis Miguel

    2006-08-21

    During cerebral ischemia, part of the damage associated with the hyperactivation of glutamate receptors results from the hyperphosphorylation of the microtubule-associated protein Tau. Previous studies have shown that estradiol treatment reduces neural damage after cerebral ischemia. Here, we show that transient occlusion of the middle cerebral artery results in the hyperphosphorylation of Tau and in a significant increase in the association of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid type glutamate receptor subunits 2/3 in the hippocampus. Estradiol treatment decreased hippocampal injury, inhibited glycogen synthase kinase-3beta and decreased the hyperphosphorylation of Tau and the interaction of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor. These findings suggest that ischemia produces a strong association between Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, and estradiol can exert at least part of its neuroprotective activity through inhibition of glycogen synthase kinase-3beta.

  10. AlphaScreen HTS and live-cell bioluminescence resonance energy transfer (BRET) assays for identification of Tau-Fyn SH3 interaction inhibitors for Alzheimer disease.

    PubMed

    Cochran, J Nicholas; Diggs, Pauleatha V; Nebane, N Miranda; Rasmussen, Lynn; White, E Lucile; Bostwick, Robert; Maddry, Joseph A; Suto, Mark J; Roberson, Erik D

    2014-12-01

    Alzheimer disease (AD) is the most common neurodegenerative disease, and with Americans' increasing longevity, it is becoming an epidemic. There are currently no effective treatments for this disorder. Abnormalities of Tau track more closely with cognitive decline than the most studied therapeutic target in AD, amyloid-β, but the optimal strategy for targeting Tau has not yet been identified. On the basis of considerable preclinical data from AD models, we hypothesize that interactions between Tau and the Src-family tyrosine kinase, Fyn, are pathogenic in AD. Genetically reducing either Tau or Fyn is protective in AD mouse models, and a dominant negative fragment of Tau that alters Fyn localization is also protective. Here, we describe a new AlphaScreen assay and a live-cell bioluminescence resonance energy transfer (BRET) assay using a novel BRET pair for quantifying the Tau-Fyn interaction. We used these assays to map the binding site on Tau for Fyn to the fifth and sixth PXXP motifs to show that AD-associated phosphorylation at microtubule affinity regulating kinase sites increases the affinity of the Tau-Fyn interaction and to identify Tau-Fyn interaction inhibitors by high-throughput screening. This screen has identified a variety of chemically tractable hits, suggesting that the Tau-Fyn interaction may represent a good drug target for AD.

  11. Persistent Sub-Yearly Chromospheric Variations in Lower Main-Sequence Stars: Tau Booe and alpha Com

    NASA Technical Reports Server (NTRS)

    Maulik, Davesh; Donahue, Robert A.; Baliunas, Sallie L.

    1997-01-01

    The recent discoveries of extrasolar planetary systems around lower main-sequence stars such as tau Booe (HD 120136) has prompted further investigation into their stellar activity. A cursory analysis of tau Booe for cyclic chromospheric activity, based on its 30-yr record of Ca 2 H and K fluxes obtained as part of the HK Project from Mount Wilson Observatory, finds an intermediate, sub-yearly period (approximately 117 d) in chromospheric activity in addition to, and separate from, both its rotation (3.3 d) and long-term variability. As a persistent subyearly period in surface magnetic activity is unprecedented, we investigate this apparent anomaly further by examining chromospheric activity levels of other stars with similar mass, searching for variability in chromospheric activity with periods of less than one year, but longer than measured or predicted rotation. An examination of the time series of 40 mid-to-late F dwarfs yielded one other star for further analysis: alpha Com (HD 114378, P approximately 132 d). The variations for these two stars were checked for persistence and coherence. Based on these determinations, we eliminate the possibilities of rotation, long-term activity cycle, and the evolution of active regions as the cause of this variation in both stars. In particular, for tau Booe we infer that the phenomenon may be chromospheric in origin; however, beyond this, it is difficult to identify anything further regarding the cause of the activity variations, or even whether the observed modulation in the two stars have the same origin.

  12. The Effects of Alpha Boswellic Acid on Reelin Expression and Tau Phosphorylation in Human Astrocytes.

    PubMed

    Fathi, Esmat; Katouli, Fatemeh Hedayati; Riazi, Gholam Hossein; Shasaltaneh, Marzieh Dehghan; Parandavar, Elham; Bayati, Samaneh; Afrasiabi, Ali; Nazari, Reza

    2017-03-01

    Reelin is an extracellular glycoprotein which contributes to synaptic plasticity and function of memory in the adult brain. It has been indicated that the Reelin signaling cascade participates in Alzheimer's disease (AD). Besides the neurons, glial cells such as astrocytes also express Reelin protein. While functional loss of astrocytes has been reported to be associated with AD, dysfunction of astrocytic Reelin signaling pathway has not received much attention. Therefore, we investigated the effects of α-boswellic acid (ABA) as one of the major component of Boswellia serrata resin on primary fetal human astrocytes under a stress paradigm as a possible model for AD through study on Reelin cascade. For this aim, we used streptozotocin (STZ), in which from an outlook generates Alzheimer's hallmarks in astrocytes, and assayed Reelin expression, Tau and Akt phosphorylation as well as reactive oxygen species (ROS) generation and apoptosis in the presences of ABA. Our results indicated that while STZ (100 µM) down-regulated the expression of Reelin, ABA (25 µM) up-regulated its expression (p < 0.01) for 24 h. ABA efficiently reduced hyperphosphorylated Tau (Ser404) in STZ-treated astrocytes (p < 0.01). Furthermore, STZ-induced apoptosis by increasing cleaved caspase three (p < 0.01) and ROS generation (p < 0.01), a further pathological hallmark of Tauopathy. On the other hand, ABA decreased ROS generation and promoted proliferation of astrocytes through elevating Survivin expression (p < 0.01). These results showed that ABA could be considered as a potent therapeutic agent for prevention and decreasing the progression of Alzheimer's hallmarks in astrocytes; however, more in vivo studies would be needed.

  13. Propene activation by the oxo-iron active species of taurine/alpha-ketoglutarate dioxygenase (TauD) enzyme. How does the catalysis compare to heme-enzymes?

    PubMed

    de Visser, Sam P

    2006-08-02

    Density functional calculations on the oxygenation reaction of propene by a model for taurine/alpha-ketoglutarate dioxygenase (TauD) enzyme are presented. The oxo-iron active species of TauD is shown to be a powerful and aggressive oxidant, which is able to hydroxylate C-H bonds and epoxidize C=C bonds with low barriers. In the case of propene oxygenation, the hydroxylation and epoxidation mechanisms are competitive on a dominant quintet spin state surface. We have compared the mechanism and thermodynamics of TauD with oxo-iron heme catalysts, such as the cytochromes P450, and found some critical differences. The TauD model is found to be much more reactive toward oxygenation of substrates than oxo-iron complexes in a heme environment with much lower reaction barriers. We have analyzed this and assigned this to the strength of the O-H bond formed after hydrogen abstraction from a substrate, which is at least 10 kcal mol(-)(1) stronger in five-coordinated oxo-iron nonheme complexes than in six-coordinated oxo-iron heme complexes. Since, the metal in TauD enzymes is five-coordinated, whereas in heme-enzymes it is six-coordinated there are some critical differences in the valence molecular orbitals. Thus, in oxo-iron heme catalysts one of the antibonding pi orbitals is replaced by a low-lying nonbonding delta orbital resulting in a lower overall spin state. Moreover, heme-enzymes have an extra oxidation equivalent located on the heme, which is missing in non-heme oxo-iron catalysts. As a result, the oxo-iron species of TauD reacts via single-state reactivity on a dominant quintet spin state surface, whereas oxo-iron heme catalysts react via two-state reactivity on competing doublet and quartet spin states.

  14. Tau physics and tau factories

    SciTech Connect

    Perl, M.L.

    1989-01-01

    Substantial progress in tau lepton physics requires larger and cleaner samples of /tau/'s produced in e/sup +/e/sup minus/ ..-->.. /tau//sup +//tau//sup minus/. Single-tagging of the /tau/ pair is crucial. Possibilities for such progress at particle factories are discussed with emphasis on the Tau-Charm Factory concept. 30 refs., 1 fig., 1 tab.

  15. Calpain- and caspase-mediated alphaII-spectrin and tau proteolysis in rat cerebrocortical neuronal cultures after ecstasy or methamphetamine exposure.

    PubMed

    Warren, Matthew W; Zheng, Wenrong; Kobeissy, Firas H; Cheng Liu, Ming; Hayes, Ronald L; Gold, Mark S; Larner, Stephen F; Wang, Kevin K W

    2007-08-01

    Abuse of 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) and methamphetamine (Meth or Speed) is a growing international problem with an estimated 250 million users of psychoactive drugs worldwide. It is important to demonstrate and understand the mechanism of neurotoxicity so potential prevention and treatment therapies can be designed. In this study rat primary cerebrocortical neuron cultures were challenged with MDMA and Meth (1 or 2 mM) for 24 and 48 h and compared to the excitotoxin N-methyl-D-aspartate (NMDA). The neurotoxicity of these drugs, as assessed by microscopy, lactate dehydrogenase release and immunoblot, was shown to be both dose- and time-dependent. Immunoblot analysis using biomarkers of cell death showed significant proteolysis of both alphaII-spectrin and tau proteins. Breakdown products of alphaII-spectrin (SBDPs) of 150, 145, and 120 kDa and tau breakdown products (TBDPs) of 45, 32, 26, and 14 kDa were observed. The use of the protease inhibitors calpain inhibitor SJA6017 and caspase inhibitors z-VAD-fmk and Z-D-DCB, attenuated drug-induced alphaII-spectrin and tau proteolysis. The calpain inhibitor reduced the calpain-induced breakdown products SBDP145 and TBDP14, but there was an offset increase in the caspase-mediated breakdown products SBDP120 and TBDP45. The caspase inhibitors, on the other hand, decreased SBDP120 and TBDP45. These data suggest that both MDMA and Meth trigger concerted proteolytic attacks of the structural proteins by both calpain and caspase family of proteases. The ability of the protease inhibitors to reduce the damage caused by these drugs suggests that the treatment arsenal could include similar drugs as possible tools to combat the drug-induced neurotoxicity in vivo.

  16. Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson's disease.

    PubMed

    Kozikowski, Alan P; Gaisina, Irina N; Petukhov, Pavel A; Sridhar, Jayalakshmi; King, LaShaunda T; Blond, Sylvie Y; Duka, Tetyana; Rusnak, Milan; Sidhu, Anita

    2006-02-01

    Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.

  17. Cerebrospinal Fluid Amyloid β1-42, Tau, and Alpha-Synuclein Predict the Heterogeneous Progression of Cognitive Dysfunction in Parkinson's Disease.

    PubMed

    Kang, Ju-Hee

    2016-05-01

    Parkinson's disease (PD) is a neurodegenerative disease with heterogeneous pathological and clinical features. Cognitive dysfunction, a frequent non-motor complication, is a risk factor for poor prognosis and shows inter-individual variation in its progression. Of the clinical studies performed to identify biomarkers of PD progression, the Parkinson's Progression Markers Initiative (PPMI) study is the largest study that enrolled drug-naïve and very early stage PD patients. The baseline characteristics of the PPMI cohort were recently published. The diagnostic utility of cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein (α-syn), total tau, phosphorylated tau at Thr181, and amyloid β1-42, was not satisfactory. However, the baseline data on CSF biomarkers in the PPMI study suggested that the measurement of the CSF biomarkers enables the prediction of future cognitive decline in PD patients, which was consistent with previous studies. To prove the hypothesis that the interaction between Alzheimer's pathology and α-syn pathology is important to the progression of cognitive dysfunction in PD, longitudinal observational studies must be followed. In this review, the neuropathological nature of heterogeneous cognitive decline in PD is briefly discussed, followed by a summarized interpretation of baseline CSF biomarkers derived from the data in the PPMI study. The combination of clinical, biochemical, genetic and imaging biomarkers of PD constitutes a feasible strategy to predict the heterogeneous progression of PD.

  18. Cerebrospinal Fluid Amyloid β1-42, Tau, and Alpha-Synuclein Predict the Heterogeneous Progression of Cognitive Dysfunction in Parkinson’s Disease

    PubMed Central

    Kang, Ju-Hee

    2016-01-01

    Parkinson’s disease (PD) is a neurodegenerative disease with heterogeneous pathological and clinical features. Cognitive dysfunction, a frequent non-motor complication, is a risk factor for poor prognosis and shows inter-individual variation in its progression. Of the clinical studies performed to identify biomarkers of PD progression, the Parkinson’s Progression Markers Initiative (PPMI) study is the largest study that enrolled drug-naïve and very early stage PD patients. The baseline characteristics of the PPMI cohort were recently published. The diagnostic utility of cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein (α-syn), total tau, phosphorylated tau at Thr181, and amyloid β1-42, was not satisfactory. However, the baseline data on CSF biomarkers in the PPMI study suggested that the measurement of the CSF biomarkers enables the prediction of future cognitive decline in PD patients, which was consistent with previous studies. To prove the hypothesis that the interaction between Alzheimer’s pathology and α-syn pathology is important to the progression of cognitive dysfunction in PD, longitudinal observational studies must be followed. In this review, the neuropathological nature of heterogeneous cognitive decline in PD is briefly discussed, followed by a summarized interpretation of baseline CSF biomarkers derived from the data in the PPMI study. The combination of clinical, biochemical, genetic and imaging biomarkers of PD constitutes a feasible strategy to predict the heterogeneous progression of PD. PMID:27240810

  19. Tau Structures

    PubMed Central

    Avila, Jesus; Jiménez, Juan S.; Sayas, Carmen L.; Bolós, Marta; Zabala, Juan C.; Rivas, Germán; Hernández, Felix

    2016-01-01

    Tau is a microtubule-associated protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. In this review, we focus on the primary, secondary, tertiary, and quaternary tau structures. We describe the structure of tau from its specific residues until its conformation in dimers, oligomers, and larger polymers in physiological and pathological situations. PMID:27877124

  20. An active-site phenylalanine directs substrate binding and C-H cleavage in the alpha-ketoglutarate-dependent dioxygenase TauD.

    PubMed

    McCusker, Kevin P; Klinman, Judith P

    2010-04-14

    Enzymes that cleave C-H bonds are often found to depend on well-packed hydrophobic cores that influence the distance between the hydrogen donor and acceptor. Residue F159 in taurine alpha-ketoglutarate dioxygenase (TauD) is demonstrated to play an important role in the binding and orientation of its substrate, which undergoes a hydrogen atom transfer to the active site Fe(IV)=O. Mutation of F159 to smaller hydrophobic side chains (L, V, A) leads to substantially reduced rates for substrate binding and for C-H bond cleavage, as well as increased contribution of the chemical step to k(cat) under steady-state turnover conditions. The greater sensitivity of these substrate-dependent processes to mutation at position 159 than observed for the oxygen activation process supports a previous conclusion of modularity of function within the active site of TauD (McCusker, K. P.; Klinman, J. P. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 19791-19795). Extraction of intrinsic deuterium kinetic isotope effects (KIEs) using single turnover transients shows 2- to 4-fold increase in the size of the KIE for F159V in relation to wild-type and F159L. It appears that there is a break in behavior following removal of a single methylene from the side chain of F159L to generate F159V, whereby the protein active site loses its ability to restore the internuclear distance between substrate and Fe(IV)=O that supports optimal hydrogenic wave function overlap.

  1. Photometric and spectroscopic monitoring of AA Tau, DN Tau, UX Tau A, T Tau, RY Tau, Lk Ca 4, and Lk Ca 7

    NASA Technical Reports Server (NTRS)

    Vrba, F. J.; Chugainov, P. F.; Weaver, W. B.; Stauffer, J. S.

    1993-01-01

    We report the results of a UBVRI photometric monitoring campaign for three classical T Tauri stars (AA Tau, DN Tau, and UX Tau A) and two weak emission line T Tauri stars (Lk Ca 4 and Lk Ca 7). Observations were obtained at three sites during a core observing period spanning UT 1985 October 14 through UT 1985 December 25, with additional observations continuing until UT 1986 April 6. Concurrent spectrophotometric observations were obtained for all main program stars except Lk Ca 7 and additionally for T Tau, RW Aur, and RY Tau. Periodic photometric variability, assumed to be the stars' rotation periods, were found for AA Tau, DN Tau, Lk Ca 4, and Lk Ca 7, respectively, as 8.2, 6.3, 3.4, and 5.7 days. Several U-filter flares were observed for Lk Ca 4 and Lk Ca 7, which are strongly concentrated toward phases of minimum light. Correlations are found between H-alpha line strengths and V magnitudes for AA Tau and RY Tau. An analysis of absolute color variations of classical T Tauri stars confirms that hot spots are the predominant cause of these stars' variability. Our overall results are consistent with earlier findings that long-lived cool spots are responsible for most of the variability found for weak-emission T Tauri stars, while temporal hot spots are primarily responsible for the observed variability found in classical T Tauri stars.

  2. Optimizing Your K-5 Engineering Design Challenge

    ERIC Educational Resources Information Center

    Coppola, Matthew Perkins; Merz, Alice H.

    2017-01-01

    Today, elementary school teachers continue to revisit old lessons and seek out new ones, especially in engineering. Optimization is the process by which an existing product or procedure is revised and refined. Drawn from the authors' experiences working directly with students in grades K-5 and their teachers and preservice teachers, the…

  3. A semiempirical atmosphere for alpha Tauri from neutral iron lines

    NASA Technical Reports Server (NTRS)

    Ramsey, L. W.

    1977-01-01

    A semiempirical model photosphere is constructed for the K5 III star Alpha Tau. The technique employed is based on measurements of the central fluxes in a series of lines in multiplets. Observations of four multiplets having a range in excitation potential yield the excitation temperature as a function of the optical depth in a reference line. If the temperature structure of an assumed starting model is changed to force agreement between the observed and predicted line source functions under the assumption that excitation and electron kinetic temperatures are equal, the final semiempirical model is cooler by 150 K in the outer layers and warmer by 150 K in deeper layers than the theoretical model with the parameters adopted for Alpha Tau.

  4. Tau Proteins Cross the Blood-Brain Barrier.

    PubMed

    Banks, William A; Kovac, Andrej; Majerova, Petra; Bullock, Kristin M; Shi, Min; Zhang, Jing

    2017-01-01

    Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer's disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151-391 (0N4R), and truncated tau 121-227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau proteins also entered the blood after their injection into the brain, with Tau 121-227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease.

  5. Tau--an inhibitor of deacetylase HDAC6 function.

    PubMed

    Perez, Mar; Santa-Maria, Ismael; Gomez de Barreda, Elena; Zhu, Xiongwei; Cuadros, Raquel; Cabrero, Jose Roman; Sanchez-Madrid, Francisco; Dawson, Hana N; Vitek, Michael P; Perry, George; Smith, Mark A; Avila, Jesus

    2009-06-01

    Analysis of brain microtubule protein from patients with Alzheimer's disease showed decreased alpha tubulin levels along with increased acetylation of the alpha tubulin subunit, mainly in those microtubules from neurons containing neurofibrillary tau pathology. To determine the relationship of tau protein and increased tubulin acetylation, we studied the effect of tau on the acetylation-deacetylation of tubulin. Our results indicate that tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity with a consequent increase in tubulin acetylation. As expected, increased acetylation was also found in tubulin from wild-type mice compared with tubulin from mice lacking tau because of the tau-mediated inhibition of the deacetylase. In addition, we found that an excess of tau protein, as a HDAC6 inhibitor, prevents induction of autophagy by inhibiting proteasome function.

  6. Comparing Fit and Reliability Estimates of a Psychological Instrument Using Second-Order CFA, Bifactor, and Essentially Tau-Equivalent (Coefficient Alpha) Models via AMOS 22

    ERIC Educational Resources Information Center

    Black, Ryan A.; Yang, Yanyun; Beitra, Danette; McCaffrey, Stacey

    2015-01-01

    Estimation of composite reliability within a hierarchical modeling framework has recently become of particular interest given the growing recognition that the underlying assumptions of coefficient alpha are often untenable. Unfortunately, coefficient alpha remains the prominent estimate of reliability when estimating total scores from a scale with…

  7. An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.

    PubMed

    Cavallini, Annalisa; Brewerton, Suzanne; Bell, Amanda; Sargent, Samantha; Glover, Sarah; Hardy, Clare; Moore, Roger; Calley, John; Ramachandran, Devaki; Poidinger, Michael; Karran, Eric; Davies, Peter; Hutton, Michael; Szekeres, Philip; Bose, Suchira

    2013-08-09

    Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.

  8. Phosphorylation of tau is regulated by PKN.

    PubMed

    Taniguchi, T; Kawamata, T; Mukai, H; Hasegawa, H; Isagawa, T; Yasuda, M; Hashimoto, T; Terashima, A; Nakai, M; Mori, H; Ono, Y; Tanaka, C

    2001-03-30

    For the phosphorylation state of microtubule-associated protein, tau plays a pivotal role in regulating microtubule networks in neurons. Tau promotes the assembly and stabilization of microtubules. The potential for tau to bind to microtubules is down-regulated after local phosphorylation. When we investigated the effects of PKN activation on tau phosphorylation, we found that PKN triggers disruption of the microtubule array both in vitro and in vivo and predominantly phosphorylates tau in microtubule binding domains (MBDs). PKN has a catalytic domain highly homologous to protein kinase C (PKC), a kinase that phosphorylates Ser-313 (= Ser-324, the number used in this study) in MBDs. Thus, we identified the phosphorylation sites of PKN and PKC subtypes (PKC-alpha, -betaI, -betaII, -gamma, -delta, -epsilon, -zeta, and -lambda) in MBDs. PKN phosphorylates Ser-258, Ser-320, and Ser-352, although all PKC subtypes phosphorylate Ser-258, Ser-293, Ser-324, and Ser-352. There is a PKN-specific phosphorylation site, Ser-320, in MBDs. HIA3, a novel phosphorylation-dependent antibody recognizing phosphorylated tau at Ser-320, showed immunoreactivity in Chinese hamster ovary cells expressing tau and the active form of PKN, but not in Chinese hamster ovary cells expressing tau and the inactive form of PKN. The immunoreactivity for phosphorylated tau at Ser-320 increased in the presence of a phosphatase inhibitor, FK506 treatment, which means that calcineurin (protein phosphatase 2B) may be involved in dephosphorylating tau at Ser-320 site. We also noted that PKN reduces the phosphorylation recognized by the phosphorylation-dependent antibodies AT8, AT180, and AT270 in vivo. Thus PKN serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly.

  9. What Renders TAU Toxic

    PubMed Central

    Götz, Jürgen; Xia, Di; Leinenga, Gerhard; Chew, Yee Lian; Nicholas, Hannah R.

    2013-01-01

    TAU is a microtubule-associated protein that under pathological conditions such as Alzheimer’s disease (AD) forms insoluble, filamentous aggregates. When 20 years after TAU’s discovery the first TAU transgenic mouse models were established, one declared goal that was achieved was the modeling of authentic TAU aggregate formation in the form of neurofibrillary tangles. However, as we review here, it has become increasingly clear that TAU causes damage much before these filamentous aggregates develop. In fact, because TAU is a scaffolding protein, increased levels and an altered subcellular localization (due to an increased insolubility and impaired clearance) result in the interaction of TAU with cellular proteins with which it would otherwise either not interact or do so to a lesser degree, thereby impairing their physiological functions. We specifically discuss the non-axonal localization of TAU, the role phosphorylation has in TAU toxicity and how TAU impairs mitochondrial functions. A major emphasis is on what we have learned from the four available TAU knock-out models in mice, and the knock-out of the TAU/MAP2 homolog PTL-1 in worms. It has been proposed that in human pathological conditions such as AD, a rare toxic TAU species exists which needs to be specifically removed to abrogate TAU’s toxicity and restore neuronal functions. However, what is toxic in one context may not be in another, and simply reducing, but not fully abolishing TAU levels may be sufficient to abrogate TAU toxicity. PMID:23772223

  10. [Phosphorylation of tau protein].

    PubMed

    Uchida, T; Ishiguro, K

    1990-05-01

    In aged human brain and particularly in Alzheimer's disease brain, paired helical filaments (PHFs) accumulate in the neuronal cell. Recently, it has been found that the highly phosphorylated tau protein, one of the microtubule-associated proteins (MAPs), is a component of PHF. The authors attempted to clarify the mechanism underlying the accumulation of PHF from the following two aspects; 1) What is the mechanism of phosphorylation of tau protein? 2) Is the highly phosphorylated tau protein capable of forming PHFs? From rat or bovine microtubule proteins we partially purified and characterized a novel protein kinase that specifically phosphorylated tau and MAP2 among many proteins in the brain extract, and which formed a PHF epitope on the phosphorylated human tau. This enzyme was one of the protein serine/threonine kinases and was independent of known second messengers. The phosphorylation of tau by this enzyme was stimulated by tubulin under the condition of microtubule formation, suggesting that the phosphorylation of tau could occur concomitantly with microtubule formation in the brain. Since this kinase was usually bound to tau but not directly to tubulin, the enzyme was associated with microtubules through tau. From these properties related to tau, this kinase is designated as tau protein kinase. The tau that been phosphorylated with this kinase using [gamma-32P]ATP as a phosphate donor, was digested by endoprotinase Lys-C to produce three labeled fragments, K1, K2 and K3. These three fragments were sequenced and the phosphorylation sites on tau by this kinase were identified. The K2 fragment overlapped with the tau-1 site known to be one of the phosphorylation site in PHF. This result strengthens the possibility that tau protein phosphorylated by tau protein kinase is incorporated into PHF. Tubulin binding sites on tau were located between K1 and K3 fragments, while K2 fragment was located in the neighboring to N-terminus of K1. No phosphorylated sites were

  11. Unraveling duality violations in hadronic tau decays

    SciTech Connect

    Cata, Oscar; Cata, Oscar; Golterman, Maarten; Peris, Santiago

    2008-03-03

    There are some indications from recent determinations of the strong coupling constant alpha_s and the gluon condensate that the Operator Product Expansion may not be accurate enough to describe non-perturbative effects in hadronic tau decays. This breakdown of the Operator Product Expansion is usually referred to as being due to"Duality Violations." With the help of a physically motivated model, we investigate these duality violations. Based on this model, we argue how they may introduce a non-negligible systematic error in the current analysis, which employs finite-energy sum rules with pinched weights. In particular, this systematic effect might affect the precision determination of alpha_s from tau decays. With a view to a possible future application to real data, we present an alternative method for determining the OPE coefficients that might help estimating, and possibly even reducing, this systematic error.

  12. Gifted Education and National Standards: A K-5 Program Evaluation

    ERIC Educational Resources Information Center

    Harwell-Braun, Debra A.

    2010-01-01

    The purpose of this study was to conduct a program evaluation of a K-5 Gifted Education Program. Program evaluation addressed how well the gifted education program studied met the National Association of Gifted Children standards. In addition, this study included stakeholder perceptions of the current gifted education program K-5. This program…

  13. Pioglitazone prevents tau oligomerization.

    PubMed

    Hamano, Tadanori; Shirafuji, Norimichi; Makino, Chiemi; Yen, Shu-Hui; Kanaan, Nicholas M; Ueno, Asako; Suzuki, Jinya; Ikawa, Masamichi; Matsunaga, Akiko; Yamamura, Osamu; Kuriyama, Masaru; Nakamoto, Yasunari

    2016-09-23

    Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.

  14. Tau polarisation at LEP

    NASA Astrophysics Data System (ADS)

    Alemany, Ricard

    1999-04-01

    The measurements of the tau polarisation at LEP I are reviewed. Special emphasis is given to the new preliminary results presented at this conference. The ALEPH collaboration has studied the polarisation as a function of the polar angle using a new method based on the tau direction reconstruction and fully exploiting the angular correlations. A second traditional approach, based on the single tau decays has been also developed. The DELPHI collaboration has also studied the full data sample using an individual tau decay method and an inclusive hadronic selection. The results from the four experiments are presented with discussion of the compatibility among the methods and experiments.

  15. Measurement of the tau lifetime

    SciTech Connect

    Jaros, J.A.

    1982-10-01

    If the tau lepton couples to the charged weak current with universal strength, its lifetime can be expressed in terms of the muon's lifetime, the ratio of the masses of the muon and the tau, and the tau's branching ratio into e anti nu/sub e/ nu/sub tau/ as tau/sub tau/ = tau/sub ..mu../ (m/sub ..mu..//m/sub tau/)/sup 5/ B(tau ..-->.. e anti nu/sub e/nu/sub tau/) = 2.8 +- 0.2 x 10/sup -13/ s. This paper describes the measurement of the tau lifetime made by the Mark II collaboration, using a new high precision drift chamber in contunction with the Mark II detector at PEP. The results of other tau lifetime measurements are summarized.

  16. Searching for anomalous {tau}{nu}W couplings

    SciTech Connect

    Rizzo, T.G.

    1997-09-01

    The capability of current and future measurements at low and high energy e{sup +}e{sup {minus}} colliders to probe for the existence of anomalous, CP-conserving, {tau}{nu}W dipole moment-type couplings is examined. At present, constraints on the universality of the {tau} charged and neutral current interactions as well as the shape of the {tau}{r_arrow}scr(l) energy spectrum provide the strongest bounds on such anomalous couplings. The presence of these dipole moments are shown to influence, e.g., the extraction of {alpha}{sub s}(m{sub {tau}}{sup 2}) from {tau} decays and can lead to apparent violations of CVC expectations. {copyright} {ital 1997} {ital The American Physical Society}

  17. An Algorithm to Find a K5 Minor

    DTIC Science & Technology

    1991-02-01

    February 1991 UILU-ENG-91-2212 ACT-117 Applied Computagion Theory AD-A232 901 AN ALGORITHM TO FIND A K5 MINOR P. J. McGuinness A. E. KezdyI DTIC...algorithm to find a K 5 minor Patrick J. McGuinness and Andr6 E. Kdzdy Abstract We present an 0(n 2) algorithm that, given a graph, either returns a K, minor...describe parallel algorithms to find Kuratowski homeomorphs and K3,3 homeomorphs, when such homeomorphs are present. Extending Kuratowski’s result, Wagner

  18. Tau protein and tau aggregation inhibitors.

    PubMed

    Bulic, Bruno; Pickhardt, Marcus; Mandelkow, Eva-Maria; Mandelkow, Eckhard

    2010-01-01

    Alzheimer disease is characterized by pathological aggregation of two proteins, tau and Abeta-amyloid, both of which are considered to be toxic to neurons. In this review we summarize recent advances on small molecule inhibitors of protein aggregation with emphasis on tau, with activities mediated by the direct interference of self-assembly. The inhibitors can be clustered in several compound classes according to their chemical structure, with subsequent description of the structure-activity relationships, showing that hydrophobic interactions are prevailing. The description is extended to the pharmacological profile of the compounds in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. The collected data indicate that following the improvements of the in vitro inhibitory potencies, the consideration of the in vivo pharmacokinetics is an absolute prerequisite for the development of compounds suitable for a transfer from bench to bedside.

  19. Measurements of the tau Mass and Mass Difference of the tau^+ and tau^- at BABAR

    SciTech Connect

    Aubert, B.; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Battaglia, M.; Brown, D.N.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; Osipenkov, I.L.; /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, San Diego /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /Harvard U. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa State U. /Iowa State U. /Johns Hopkins U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT /McGill U. /INFN, Milan /Milan U. /INFN, Milan /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /Mt. Holyoke Coll. /INFN, Naples /Naples U. /INFN, Naples /INFN, Naples /Naples U. /NIKHEF, Amsterdam /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Padua /Padua U. /INFN, Padua /INFN, Padua /Padua U. /Paris U., VI-VII /Pennsylvania U. /INFN, Perugia /Perugia U. /INFN, Pisa /Pisa U. /INFN, Pisa /Pisa, Scuola Normale Superiore /INFN, Pisa /Pisa U. /INFN, Pisa /Princeton U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /Rostock U. /Rutherford /DAPNIA, Saclay /SLAC /South Carolina U. /Stanford U., Phys. Dept. /SUNY, Albany /Tel Aviv U. /Tennessee U. /Texas U. /Texas U., Dallas /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /Valencia U. /Victoria U. /Warwick U. /Wisconsin U., Madison

    2009-10-30

    The authors present the result of a precision measurement of the mass of the {tau} lepton, M{sub {tau}}, based on 423 fb{sup -1} of data recorded at the {Upsilon}(4S) resonance with the BABAR detector. Using a pseudomass endpoint method, they determine the mass to be 1776.68 {+-} 0.12(stat) {+-} 0.41(syst) MeV. They also measure the mass difference between the {tau}{sup +} and {tau}{sup -}, and obtain (M{sub {tau}{sup +}} - M{sub {tau}{sup -}})/M{sub AVG}{sup {tau}} = (-3.4 {+-} 1.3(stat) {+-} 0.3(syst)) x 10{sup -4}, where M{sub AVG}{sup {tau}} is the average value of M{sub {tau}{sup +}} and M{sub {tau}{sup -}}.

  20. Bringing History Home: A K-5 Curriculum Design

    ERIC Educational Resources Information Center

    Fillpot, Elise

    2009-01-01

    Bringing history home, an elementary history curriculum and professional development project, began in 2001. As originally conceived, the project's main purpose was to move history from the margins described by Bruce VanSledright into the mainstream of the K-5 school day. Seven years later, the Bringing History Home (BHH) instructional units are…

  1. Math and Economics: Implementing Authentic Instruction in Grades K-5

    ERIC Educational Resources Information Center

    Althauser, Krista; Harter, Cynthia

    2016-01-01

    The purpose of this study is to outline a partnership program that involved a local elementary school district, an institution of higher education, the local business community, and a state economic education advocacy group to integrate economics into math in grades K-5. The "Economics: Math in Real Life" program was provided in…

  2. The Common Core: Insights into the K-5 Standards

    ERIC Educational Resources Information Center

    McLaughlin, Maureen; Overturf, Brenda J.

    2012-01-01

    The role of the Common Core English Language Arts Standards in grades K-5 literacy instruction is the focus of the article. The authors begin by raising four questions: (1) What is the essential philosophy of the Common Core State Standards?; (2) What do educators need to know to use the College and Career Readiness Standards and Common Core State…

  3. Juneau Indian Studies Elementary Curriculum Guide. Grades K-5.

    ERIC Educational Resources Information Center

    Cadiente, Ronalda

    Designed to provide instruction in Tlingit culture as an integral part of the K-5 social studies curriculum, this guide presents teachers with extensive lesson plans and numerous resource materials. The units of study focus on the culture and environment of southeast Alaska and emphasize experiential learning activities. Each grade…

  4. Tau physics results from SLD

    SciTech Connect

    Daoudi, M.; SLD Collaboration

    1996-08-10

    Results on {tau} physics at SLD are presented. They are based on 4,316 {tau}-pair events selected from a 150 k Z{sup 0} data sample collected at the SLC. These results include measurements of the {tau} lifetime ({tau}{sub r} = 288.1 {+-} 6.1 {+-} 3.3 fs), the {tau} Michel parameters ({rho} = 0.71 {+-} 0.09 {+-} 0.04, {zeta} = 1.03 {+-} 0.36 {+-} 0.05, and {zeta}{delta} = 0.84 {+-} 0.27 {+-} 0.05), and the {tau} neutrino helicity (h{sub {nu}} = {minus}0.81 {+-} 0.18 {+-} 0.03).

  5. [Anti-HIV effects of IFN-tau in human macrophages: role of cellular antiviral factors and interleukin-6].

    PubMed

    Maneglier, B; Rogez-Kreuz, C; Dereuddre-Bosquet, N; Martal, J; Devillier, P; Dormont, D; Clayette, P

    2008-01-01

    Tau interferon (IFN-tau) was shown to inhibit human immunodeficiency virus (HIV) replication in vitro more strongly than human IFN-alpha, particularly in human macrophages. IFN-tau efficiently inhibited the early steps of HIV biological cycle, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. In this study, the in vitro immunomodulatory effects of IFN-tau were explored in human macrophages. We found that IFN-tau increased the synthesis of the cellular antiviral factors, such as 2',5'-oligoadenylate synthetase/RNase L and MxA protein. These results suggested that IFN-tau induces the same antiviral pathways in macrophages as other type I IFNs. We found that IFN-tau increased the production of interleukins (IL)-10 and IL-6, but not of IL-1ss or TNF-alpha, in not infected and in in vitro HIV-1/Ba-L-infected macrophages. We also found that the neutralization of IL-6 biological activity in the cell culture supernatants of IFN-tau-treated macrophages led to a decrease in the antiretroviral effects of IFN-tau towards HIV RNA. In conclusion, anti-HIV effects of IFN-tau are mediated by several modes of action, mediated either directly by IFN-tau or via other cytokines, such as IL-6, also known to be induced by IFN-alpha.

  6. A novel tau-tubulin kinase from bovine brain.

    PubMed

    Takahashi, M; Tomizawa, K; Sato, K; Ohtake, A; Omori, A

    1995-09-18

    During purification of tau protein kinase I and II from the bovine brain extract, a new tau protein kinase was detected and purified with phosphocellulose, gel filtration, S-Sepharose and AF-Heparin column chromatography. The molecular mass of the enzyme was determined to be 32 kDa by gel filtration and activity staining on SDS-PAGE. The enzyme is a Ser/Thr protein kinase phosphorylating tau, beta-tubulin, MAP2 and alpha-casein. Employing many synthetic peptides, the recognition site of this enzyme appears to be -SR-. The enzyme requires no second messenger and is inhibited with high concentration of heparin, but not by inhibitors of CKI. These results indicate that this enzyme, tau-tubulin kinase is novel and distinct from TPKI, II and CKI, II.

  7. Review of tau lepton decays

    SciTech Connect

    Stoker, D.P.

    1991-07-01

    Measurements of the {tau} decay modes are reviewed and compared with the predictions of the Standard Model. While the agreement is generally good, the status of the 1-prong puzzle'' remains controversial and a discrepancy between the measured leptonic branching fractions and the {tau} lifetime persists. Prospects for precision measurements at a Tau-Charm Factory are also reviewed. 20 refs., 2 tabs.

  8. Measurements of the decays tau/sup -/. -->. rho/sup -/. nu. /sub tau/, tau/sup -/. -->. pi. /sup -/. nu. /sub tau/ and tau/sup -/. -->. K*-(892). nu. /sub tau/ using the MARK II detector at SPEAR

    SciTech Connect

    Dorfan, J.

    1981-04-01

    Measurements of the branching fractions for the Cabibbo favored decays tau/sup -/ ..-->.. rho/sup -/ ..-->.. ..pi../sup -/..nu../sub tau/ and the Cabibbo suppressed decay mode tau/sup -/ ..-->.. K*/sup -/ (892)..nu../sub tau/ are presented. The energy dependence of the tau/sup +/tau/sup -/ production cross section is obtained for the decays tau/sup -/ ..-->.. rho/sup -/..nu../sub tau/ and these spectra agree well with the classification of the tau/sup -/ as a spin-1/2 point particle. Fits to the production cross section yield a measurement of M/sub tau/ = (1787 +- 10) MeV/c/sup 2/ for the tau mass. Ninety-five percent confidence upper limits for the forbidden decay tau/sup -/ ..-->.. K*/sup -/(1430)..nu../sub tau/ and the tau neutrino mass are presented.

  9. YES 2K5: Young Engineers and Scientists Mentorship Program

    NASA Astrophysics Data System (ADS)

    Boice, D. C.; Asbell, H. E.

    2005-12-01

    The Young Engineers and Scientists (YES) Program is a community partnership between Southwest Research Institute (SwRI), and local high schools in San Antonio, Texas (USA). YES has been highly successful during the past 13 years, and YES 2K5 continued this trend. It provides talented high school juniors and seniors a bridge between classroom instruction and real-world, research experiences in physical sciences (including space science and astronomy) and engineering. YES 2K5 consists of two parts: 1) an intensive three-week summer workshop held at SwRI where students experience the research environment first-hand; develop skills and acquire tools for solving scientific problems, attend mini-courses and seminars on electronics, computers and the Internet, careers, science ethics, and other topics; and select individual research projects to be completed during the academic year; and 2) a collegial mentorship where students complete individual research projects under the guidance of their mentors during the academic year and earn honors credit. At the end of the school year, students publicly present and display their work, acknowledging their accomplishments and spreading career awareness to other students and teachers. YES 2K5 developed a website for the Magnetospheric Multiscale Mission (MMS) from the perspective of a high school student. Over the past 13 years, all YES graduates have entered college, several have worked for SwRI, and three scientific publications have resulted. Student evaluations indicate the effectiveness of YES on their academic preparation and choice of college majors. We acknowledge funding from the NASA MMS Mission, the NASA E/PO program, and local charitable foundations.

  10. Neuronal activity enhances tau propagation and tau pathology in vivo.

    PubMed

    Wu, Jessica W; Hussaini, S Abid; Bastille, Isle M; Rodriguez, Gustavo A; Mrejeru, Ana; Rilett, Kelly; Sanders, David W; Cook, Casey; Fu, Hongjun; Boonen, Rick A C M; Herman, Mathieu; Nahmani, Eden; Emrani, Sheina; Figueroa, Y Helen; Diamond, Marc I; Clelland, Catherine L; Wray, Selina; Duff, Karen E

    2016-08-01

    Tau protein can transfer between neurons transneuronally and trans-synaptically, which is thought to explain the progressive spread of tauopathy observed in the brain of patients with Alzheimer's disease. Here we show that physiological tau released from donor cells can transfer to recipient cells via the medium, suggesting that at least one mechanism by which tau can transfer is via the extracellular space. Neuronal activity has been shown to regulate tau secretion, but its effect on tau pathology is unknown. Using optogenetic and chemogenetic approaches, we found that increased neuronal activity stimulates the release of tau in vitro and enhances tau pathology in vivo. These data have implications for disease pathogenesis and therapeutic strategies for Alzheimer's disease and other tauopathies.

  11. Melasma: successful treatment with pidobenzone 4% (K5lipogel).

    PubMed

    Zanieri, Fabio; Assad, Gelareh Bani; Campolmi, Piero; Lotti, Torello

    2008-07-01

    Melasma (a term derived from the Greek word "melas" meaning black) is an acquired blotchy, irregularly patterned, brown or sometimes gray brown hypermelanosis of the face and occasionally the neck. Its etiology is poorly understood but mainly related to sunlight and genetic predisposition. Melasma seems to be more frequent in darker skinned people, especially women. Its treatment is always difficult and the condition usually relapses. The treatment with pidobenzone 4% (K5 lipogel), twice per day for 16 weeks has proved to be safe and effective. Pidobenzone 4% lipogel, according to the present study, seems also to represent a useful, reliable, and safe treatment of the different types of melasma.

  12. A High-throughput Screening Assay for Determining Cellular Levels of Total Tau Protein

    PubMed Central

    Dehdashti, Seameen J.; Zheng, Wei; Gever, Joel R.; Wilhelm, Robert; Nguyen, Dac-Trung; Sittampalam, Gurusingham; McKew, John C.; Austin, Christopher P.; Prusiner, Stanley B.

    2014-01-01

    The microtubule-associated protein (MAP) tau has been implicated in the pathology of numerous neurodegenerative diseases. In the past decade, the hyperphosphorylated and aggregated states of tau protein have been important targets in the drug discovery field for the potential treatment of Alzheimer’s disease. Although several compounds have been reported to reduce the hyperphosphorylated state of tau or impact the stabilization of tau, their therapeutic activities are still to be validated. Recently, reduction of total cellular tau protein has emerged as an alternate intervention point for drug development and a potential treatment of tauopathies. We have developed and optimized a homogenous assay, using the AlphaLISA and HTRF assay technologies, for the quantification of total cellular tau protein levels in the SH-SY5Y neuroblastoma cell line. The signal-to-basal ratios were 375 and 5.3, and the Z’ factors were 0.67 and 0.60 for the AlphaLISA and HTRF tau assays, respectively. The clear advantages of this homogeneous tau assay over conventional total tau assays, such as ELISA and Western blot, are the elimination of plate wash steps and miniaturization of the assay into 1536-well plate format for the ultra–high-throughput screening of large compound libraries. PMID:23905996

  13. Gamma (K5 Based) Compressor Blade Material Design - Alpha Extrusion on a Small Scale

    NASA Technical Reports Server (NTRS)

    Kim, Young-Won

    2003-01-01

    The objective of the 2003 study is to develop a mechanically processed, high temperature TiAl alloy for use in the Turbine Based Combined Cycle compressor. An aging study with 3 temperatures and 4 time periods at each temperature will be conducted to determine the optimum aging condition. High-magnification microscopic analyses shall be employed to define the size distribution of carbide as a function of aging temperature/time. The contractor shall define optimum materials' conditions by conducting tensile and creep testing for two over-aging conditions for both alloys and fatigue testing for one over-aging condition for each alloy.

  14. Boronate-tau mediated uptake in neurons.

    PubMed

    Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemi; García, Carlos; Langa, Elena; Jurado-Arjona, Jerónimo; Hernández, Félix; Avila, Jesús

    2014-01-01

    We modified tau protein with boronic acid to facilitate its delivery into non neural or neural cultured cells lacking tau protein. Our results indicate that the incorporated tau promotes the formation of cytoplasmic extensions in non-neuronal cells, as well as the appearance of neurites in cultured tau knockout hippocampal neurons. In addition, boronated tau is incorporated into hippocampal neurons of tau knockout mice after intracranial injection in vivo. These findings describe a novel method to deliver exogenous tau protein into cells.

  15. Leptonic CP violation induced by approximately {mu}-{tau} symmetric seesaw mechanism

    SciTech Connect

    Baba, Teppei; Yasue, Masaki

    2008-04-01

    Assuming a minimal seesaw model with two heavy neutrinos (N), we examine effects of leptonic CP violation induced by approximate {mu}-{tau} symmetric interactions. As long as N is subject to the {mu}-{tau} symmetry, we can choose CP phases of Dirac mass terms without loss of generality in such a way that these phases arise from {mu}-{tau} symmetry breaking interactions. In the case that no phase is present in heavy neutrino mass terms, leptonic CP phases are controlled by two phases {alpha} and {beta}. The similar consideration is extended to N blind to the {mu}-{tau} symmetry. It is argued that N subject (blind) to the {mu}-{tau} symmetry necessarily describes the normal (inverted) mass hierarchy. We restrict ourselves to {mu}-{tau} symmetric textures giving the tribimaximal mixing and calculate flavor neutrino masses to estimate CP-violating Dirac and Majorana phases as well as neutrino mixing angles as functions of {alpha} and {beta}. Since {alpha} and {beta} are generated by {mu}-{tau} symmetry breaking interactions, the CP-violating Majorana phase tends to be suppressed and is found to be at most O(0.1) radian. On the other hand, the CP-violating Dirac phase tends to show a proportionality to {alpha} or to {beta}.

  16. Plasma tau in Alzheimer disease

    PubMed Central

    Zetterberg, Henrik; Janelidze, Shorena; Insel, Philip S.; Andreasson, Ulf; Stomrud, Erik; Palmqvist, Sebastian; Baker, David; Tan Hehir, Cristina A.; Jeromin, Andreas; Hanlon, David; Song, Linan; Shaw, Leslie M.; Trojanowski, John Q.; Weiner, Michael W.; Hansson, Oskar; Blennow, Kaj

    2016-01-01

    Objective: To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism. Methods: This was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition. Results: Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up. Conclusions: Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD. PMID:27694257

  17. Results of tests of weathered K5NA closeout material in the MSFC Hot Gas Facility

    NASA Technical Reports Server (NTRS)

    Dean, W. G.

    1982-01-01

    The application of K5NA over hypolon was investigated. The effects of using K5NA over painted cork surfaces, the effects of weathering on the unpainted K5NA surfaces are determined, and the use of water versus solvent for tooling K5NA in place were compared. It is concluded that: (1) K5NA can be applied to hypalon surfaces; (2) K5NA can be left unpainted; and (3) K5NA can be tested with water or solvent.

  18. Decays of the heavy lepton, tau (1785)

    SciTech Connect

    Blocker, C.A.

    1980-04-01

    The structure of the weak hadronic current coupled to the tau is investigated via some of the hadronic decays of the tau. The vector current coupling is determined by measuring the tau ..-->.. rho ..nu../sub tau/ branching ratio. The axial-vector coupling is determined by measuring the tau ..-->.. ..pi.. ..nu../sub tau/ branching ratio. The Cabibbo structure of the hadronic current is established by observing the decay tau ..-->.. K*(890)..nu../sub tau/ and measuring its branching ratio. The branching ratios for the decays tau ..-->.. e anti ..nu../sub e/..nu../sub tau/ and tau ..-->.. ..mu.. anti ..nu../sub ..mu../..nu../sub tau/ are measured as a normalization for the hadronic decays and as a check on the validity of the measurements. The leptonic branching ratios agree well with previous experiments. From a kinematic fit to the pion energy spectrum in the decay tau ..-->.. ..pi.. ..nu../sub tau/, an upper limit (95% confidence level) of 245 MeV is placed on the tau neutrino mass. From a simultaneous fit of the center of mass energy dependence of the tau production cross section and the pion energy spectrum in the decay tau ..-->.. ..pi.. ..nu../sub tau/, the tau mass is determined to be 1.787 +- .010 GeV/c. All properties of the tau measured here are consistent with it being a sequential lepton coupled to the ordinary weak hadronic current.

  19. Tau immunotherapy for Alzheimer's disease.

    PubMed

    Pedersen, Jan Torleif; Sigurdsson, Einar M

    2015-06-01

    Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-β (Aβ) plaques, their clearance may be clinically more efficacious than removing Aβ when cognitive deficits become evident in AD. Several complementary mechanisms of antibody-mediated removal of tau aggregates are likely to act in concert and the importance of each one may depend on antibody properties, the disease, and its stage. Clinical trials of tau immunotherapy are already underway and several more are likely to be initiated in the near future.

  20. Effects of tau domain-specific antibodies and intravenous immunoglobulin on tau aggregation and aggregate degradation.

    PubMed

    Esteves-Villanueva, Jose O; Trzeciakiewicz, Hanna; Loeffler, David A; Martić, Sanela

    2015-01-20

    Tau pathology, including neurofibrillary tangles, develops in Alzheimer's disease (AD). The aggregation and hyperphosphorylation of tau are potential therapeutic targets for AD. Administration of anti-tau antibodies reduces tau pathology in transgenic "tauopathy" mice; however, the optimal tau epitopes and conformations to target are unclear. Also unknown is whether intravenous immunoglobulin (IVIG) products, currently being evaluated in AD trials, exert effects on pathological tau. This study examined the effects of anti-tau antibodies targeting different tau epitopes and the IVIG Gammagard on tau aggregation and preformed tau aggregates. Tau aggregation was assessed by transmission electron microscopy and fluorescence spectroscopy, and the binding affinity of the anti-tau antibodies for tau was evaluated by enzyme-linked immunosorbent assays. Antibodies used were anti-tau 1-150 ("D-8"), anti-tau 259-266 ("Paired-262"), anti-tau 341-360 ("A-10"), and anti-tau 404-441 ("Tau-46"), which bind to tau's N-terminus, microtubule binding domain (MBD) repeat sequences R1 and R4, and the C-terminus, respectively. The antibodies Paired-262 and A-10, but not D-8 and Tau-46, reduced tau fibrillization and degraded preformed tau aggregates, whereas the IVIG reduced tau aggregation but did not alter preformed aggregates. The binding affinities of the antibodies for the epitope for which they were specific did not appear to be related to their effects on tau aggregation. These results confirm that antibody binding to tau's MBD repeat sequences may inhibit tau aggregation and indicate that such antibodies may also degrade preformed tau aggregates. In the presence of anti-tau antibodies, the resulting tau morphologies were antigen-dependent. The results also suggested the possibility of different pathways regulating antibody-mediated inhibition of tau aggregation and antibody-mediated degradation of preformed tau aggregates.

  1. Survivability of Psychrobacter cryohalolentis K5 under simulated martian surface conditions.

    PubMed

    Smith, David J; Schuerger, Andrew C; Davidson, Mark M; Pacala, Stephen W; Bakermans, Corien; Onstott, Tullis C

    2009-03-01

    Spacecraft launched to Mars can retain viable terrestrial microorganisms on board that may survive the interplanetary transit. Such biota might compromise the search for life beyond Earth if capable of propagating on Mars. The current study explored the survivability of Psychrobacter cryohalolentis K5, a psychrotolerant microorganism obtained from a Siberian permafrost cryopeg, under simulated martian surface conditions of high ultraviolet irradiation, high desiccation, low temperature, and low atmospheric pressure. First, a desiccation experiment compared the survival of P. cryohalolentis cells embedded, or not embedded, within a medium/salt matrix (MSM) maintained at 25 degrees C for 24 h within a laminar flow hood. Results indicate that the presence of the MSM enhanced survival of the bacterial cells by 1 to 3 orders of magnitude. Second, tests were conducted in a Mars Simulation Chamber to determine the UV tolerance of the microorganism. No viable vegetative cells of P. cryohalolentis were detected after 8 h of exposure to Mars-normal conditions of 4.55 W/m(2) UVC irradiation (200-280 nm), -12.5 degrees C, 7.1 mbar, and a Mars gas mix composed of CO(2) (95.3%), N(2) (2.7%), Ar (1.6%), O(2) (0.2%), and H(2)O (0.03%). Third, an experiment was conducted within the Mars chamber in which total atmospheric opacities were simulated at tau = 0.1 (dust-free CO(2) atmosphere at 7.1 mbar), 0.5 (normal clear sky with 0.4 = dust opacity and 0.1 = CO(2)-only opacity), and 3.5 (global dust storm) to determine the survivability of P. cryohalolentis to partially shielded UVC radiation. The survivability of the bacterium increased with the level of UVC attenuation, though population levels still declined several orders of magnitude compared to UVC-absent controls over an 8 h exposure period.

  2. Survivability of Psychrobacter cryohalolentis K5 Under Simulated Martian Surface Conditions

    NASA Technical Reports Server (NTRS)

    Smith, David J.; Schuerger, Andrew C.; Davidson, Mark M.; Pacala, Stephen W.; Bakermans, Corien; Onstott, Tullis

    2008-01-01

    Spacecraft launched to Mars can retain viable terrestrial microorganisms on board that may survive the interplanetary transit. Such biota might compromise the search for life beyond Earth if capable of propagating on Mars. The current study explored the survivability of Psychrobacter cryohalolentis K5, a psychrotolerant microorganism obtained from a Siberian permafrost cryopeg, under simulated martian surface conditions of high ultraviolet irradiation, high desiccation, low temperature, and low atmospheric pressure. First, a desiccation experiment compared the survival of P. cryohalolentis cells embedded, or not embedded, within a medium/salt matrix (MSM) maintained at 25 degrees C for 24 hr within a laminar flow hood. Results indicate that the presence of the MSM enhanced survival of the bacterial cells by 1 to 3 orders of magnitude. Second, tests were conducted in a Mars Simulation Chamber to determine the UV tolerance of the microorganism. No viable vegetative cells of P. cryohalolentis were detected after 8 hr of exposure to Mars-normal conditions of 4.55 W/m(2) UVC irradiation (200-280 nm), -12.5 degrees C, 7.1 mbar, and a Mars gas mix composed of CO2 (95.3%), N2 (2.7%), Ar (1.6%), O2 (0.2%), and H(2)O (0.03%). Third, an experiment was conducted within the Mars chamber in which total atmospheric opacities were simulated at tau = 0.1 (dust-free CO2 atmosphere at 7.1 mbar), 0.5 (normal clear sky with 0.4 = dust opacity and 0.1 = CO2-only opacity), and 3.5 (global dust storm) to determine the survivability of P. cryohalolentis to partially shielded UVC radiation. The survivability of the bacterium increased with the level of UVC attenuation, though population levels still declined several orders of magnitude compared to UVC-absent controls over an 8 hr exposure period.

  3. Tau identification at the Tevatron

    SciTech Connect

    Levy, Stephen; /Chicago U., EFI

    2005-07-01

    Methods for reconstructing and identifying the hadronic decays of tau leptons with the CDF and D0 detectors at the Fermilab Tevatron collider in Run II are described. Precision electroweak measurements of W and Z gauge boson cross sections are presented as well as results of searches for physics beyond the Standard Model with hadronically decaying tau leptons in the final state.

  4. Interactions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease

    PubMed Central

    Roy, Bidisha; Jackson, George R.

    2014-01-01

    Clinical and pathological studies have suggested considerable overlap between tauopathies and synucleinopathies. Several genome-wide association studies have identified alpha-Synuclein (SNCA) and Tau (MAPT) polymorphisms as common risk factors for sporadic Parkinson's disease (PD). However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear. To examine causes of neurotoxicity associated with the α-Syn/Tau interaction, we used the fruit fly as a model. We utilized misexpression paradigms in three different tissues to probe the α-Syn/Tau interaction: the retina, dopaminergic neurons and the larval neuromuscular junction. Misexpression of Tau and α-Syn enhanced a rough eye phenotype and loss of dopaminergic neurons in fly tauopathy and synucleinopathy models, respectively. Our findings suggest that interactions between α-Syn and Tau at the cellular level cause disruption of cytoskeletal organization, axonal transport defects and aberrant synaptic organization that contribute to neuronal dysfunction and death associated with sporadic PD. α-Syn did not alter levels of Tau phosphorylated at the AT8 epitope. However, α-Syn and Tau colocalized in ubiquitin-positive aggregates in eye imaginal discs. The presence of Tau also led to an increase in urea soluble α-Syn. Our findings have important implications in understanding the cellular and molecular mechanisms underlying α-Syn/Tau-mediated synaptic dysfunction, which likely arise in the early asymptomatic phase of sporadic PD. PMID:24430504

  5. Using Human iPSC-Derived Neurons to Model TAU Aggregation.

    PubMed

    Verheyen, An; Diels, Annick; Dijkmans, Joyce; Oyelami, Tutu; Meneghello, Giulia; Mertens, Liesbeth; Versweyveld, Sofie; Borgers, Marianne; Buist, Arjan; Peeters, Pieter; Cik, Miroslav

    2015-01-01

    Alzheimer's disease and frontotemporal dementia are amongst the most common forms of dementia characterized by the formation and deposition of abnormal TAU in the brain. In order to develop a translational human TAU aggregation model suitable for screening, we transduced TAU harboring the pro-aggregating P301L mutation into control hiPSC-derived neural progenitor cells followed by differentiation into cortical neurons. TAU aggregation and phosphorylation was quantified using AlphaLISA technology. Although no spontaneous aggregation was observed upon expressing TAU-P301L in neurons, seeding with preformed aggregates consisting of the TAU-microtubule binding repeat domain triggered robust TAU aggregation and hyperphosphorylation already after 2 weeks, without affecting general cell health. To validate our model, activity of two autophagy inducers was tested. Both rapamycin and trehalose significantly reduced TAU aggregation levels suggesting that iPSC-derived neurons allow for the generation of a biologically relevant human Tauopathy model, highly suitable to screen for compounds that modulate TAU aggregation.

  6. Using Human iPSC-Derived Neurons to Model TAU Aggregation

    PubMed Central

    Verheyen, An; Diels, Annick; Dijkmans, Joyce; Oyelami, Tutu; Meneghello, Giulia; Mertens, Liesbeth; Versweyveld, Sofie; Borgers, Marianne; Buist, Arjan; Peeters, Pieter; Cik, Miroslav

    2015-01-01

    Alzheimer’s disease and frontotemporal dementia are amongst the most common forms of dementia characterized by the formation and deposition of abnormal TAU in the brain. In order to develop a translational human TAU aggregation model suitable for screening, we transduced TAU harboring the pro-aggregating P301L mutation into control hiPSC-derived neural progenitor cells followed by differentiation into cortical neurons. TAU aggregation and phosphorylation was quantified using AlphaLISA technology. Although no spontaneous aggregation was observed upon expressing TAU-P301L in neurons, seeding with preformed aggregates consisting of the TAU-microtubule binding repeat domain triggered robust TAU aggregation and hyperphosphorylation already after 2 weeks, without affecting general cell health. To validate our model, activity of two autophagy inducers was tested. Both rapamycin and trehalose significantly reduced TAU aggregation levels suggesting that iPSC-derived neurons allow for the generation of a biologically relevant human Tauopathy model, highly suitable to screen for compounds that modulate TAU aggregation. PMID:26720731

  7. Increased suppression of oncolytic adenovirus carrying mutant k5 on colorectal tumor

    SciTech Connect

    Fan Junkai; Xiao Tian; Gu Jinfa; Wei Na; He Lingfeng; Ding Miao; Liu Xinyuan

    2008-09-19

    Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth.

  8. CP violation in hadronic {tau} decays

    SciTech Connect

    Datta, Alakabha; Kiers, Ken; London, David; Szynkman, Alejandro; O'Donnell, Patrick J.

    2007-04-01

    We reexamine CP violation in the {delta}S=0 decays {tau}{yields}N{pi}{nu}{sub {tau}} (N=2,3,4). We assume that the new physics (NP) is a charged Higgs boson. We show that there is no NP contribution to {tau}{yields}{pi}{pi}{nu}{sub {tau}}, which means that no CP violation is expected in this decay. On the other hand, NP can contribute to {tau}{yields}N{pi}{nu}{sub {tau}} (N=3,4). These are dominated by the intermediate resonant decays {tau}{yields}{omega}{pi}{nu}{sub {tau}}, {tau}{yields}{rho}{pi}{nu}{sub {tau}}, and {tau}{yields}a{sub 1}{pi}{nu}{sub {tau}}. We show that the only sizeable CP-violating effects which are possible are in {tau}{yields}a{sub 1}{pi}{nu}{sub {tau}}{yields}4{pi}{nu}{sub {tau}} (polarization-dependent rate asymmetry) and {tau}{yields}{omega}{pi}{nu}{sub {tau}} (triple-product asymmetry)

  9. 29 CFR 71.52 - Specific exemptions pursuant to subsection (k)(5) of the Privacy Act.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Specific exemptions pursuant to subsection (k)(5) of the... § 71.52 Specific exemptions pursuant to subsection (k)(5) of the Privacy Act. (a) The following systems of records are eligible for exemption under 5 U.S.C. 552a(k)(5) because they contain...

  10. 26 CFR 1.401(k)-5 - Special rules for mergers, acquisitions and similar events. [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Special rules for mergers, acquisitions and similar events. 1.401(k)-5 Section 1.401(k)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE.... § 1.401(k)-5 Special rules for mergers, acquisitions and similar events....

  11. 26 CFR 1.401(k)-5 - Special rules for mergers, acquisitions and similar events. [Reserved

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 5 2014-04-01 2014-04-01 false Special rules for mergers, acquisitions and similar events. 1.401(k)-5 Section 1.401(k)-5 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE... Plans, Etc. § 1.401(k)-5 Special rules for mergers, acquisitions and similar events....

  12. Changes in tau phosphorylation in hibernating rodents.

    PubMed

    León-Espinosa, Gonzalo; García, Esther; García-Escudero, Vega; Hernández, Félix; Defelipe, Javier; Avila, Jesús

    2013-07-01

    Tau is a cytoskeletal protein present mainly in the neurons of vertebrates. By comparing the sequence of tau molecule among different vertebrates, it was found that the variability of the N-terminal sequence in tau protein is higher than that of the C-terminal region. The N-terminal region is involved mainly in the binding of tau to cellular membranes, whereas the C-terminal region of the tau molecule contains the microtubule-binding sites. We have compared the sequence of Syrian hamster tau with the sequences of other hibernating and nonhibernating rodents and investigated how differences in the N-terminal region of tau could affect the phosphorylation level and tau binding to cell membranes. We also describe a change, in tau phosphorylation, on a casein kinase 1 (ck1)-dependent site that is found only in hibernating rodents. This ck1 site seems to play an important role in the regulation of tau binding to membranes.

  13. Hadronic Tau Decays at BaBar

    SciTech Connect

    Nugent, I.M.; /Victoria U.

    2007-10-25

    Precision measurements of the exclusive branching fraction {tau}{sup -} {yields} K{sup -}{pi}{sup 0}{nu}{sub {tau}} and {tau}{sup -} {yields} h{sup -}h{sup -}h{sup +}{nu}{sub {tau}}, where the h represent either a pion or a kaon, from the BABAR Experiment are presented. The branching fraction for {tau}{sup -} {yields} K{sup -}K{sup -}K{sup +}{nu}{sub {tau}} is the first resonant plus non-resonant measurement of this mode and the branching fraction {tau}{sup -} {yields} {phi}{pi}{sup -}{nu}{sub {tau}} is also a first measurement. In addition we present the new measurement of the branching fraction of {tau}{sup -} {yields} {phi}K{sup -}{nu}{sub {tau}}.

  14. The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury

    PubMed Central

    Collino, Massimo; Pini, Alessandro; Mastroianni, Rosanna; Benetti, Elisa; Lanzi, Cecilia; Bani, Daniele; Chini, Jacopo; Manoni, Marco; Fantozzi, Roberto; Masini, Emanuela

    2012-01-01

    Heparin and low molecular weight heparins have been demonstrated to reduce myocardial ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhagic and thrombotic complications. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility of producing heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of regional myocardial I/R, we investigated the effects of an epimerized N-,O-sulphated K5 polysaccharide derivative, K5-N,OSepi, on infarct size and histological signs of myocardial injury caused by 30 min. ligature of the left anterior descending coronary artery followed by 1 or 24 h reperfusion. K5-N,OSepi (0.1–1 mg/kg given i.v. 15 min. before reperfusion) significantly reduced the extent of myocardial damage in a dose-dependent manner. Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by K5-N,OSepi. In left ventricular samples, I/R induced mast cell degranulation and a robust increase in lipid peroxidation, free radical-induced DNA damage and calcium overload. Markers of neutrophil infiltration and activation were also induced by I/R in rat hearts, specifically myeloperoxidase activity, intercellular-adhesion-molecule-1 expression, prostaglandin-E2 and tumour-necrosis-factor-α production. The robust increase in oxidative stress and inflammatory markers was blunted by K5-N,OSepi, in a dose-dependent manner, with maximum at 1 mg/kg. Furthermore, K5-N,OSepi administration attenuated the increase in caspase 3 activity, Bid and Bax activation and ameliorated the decrease in expression of Bcl-2 within the ischaemic myocardium. In conclusion, we demonstrate that the cardioprotective effect of the non-anticoagulant K5 derivative K5-N,OSepi is secondary to a combination of anti-apoptotic and anti-inflammatory effects. PMID:22248092

  15. First results from the Goddard High-Resolution Spectrograph - The chromosphere of Alpha Tauri

    NASA Technical Reports Server (NTRS)

    Carpenter, Kenneth G.; Robinson, Richard D.; Wahlgren, Glenn M.; Ake, Thomas B.; Ebbets, Dennis C.

    1991-01-01

    The K5 III star Alpha Tau was observed with the Goddard High Resolution Spectrograph on November 27, 1990 as part of the Science Assessment Program for the HST. The spectra show intersystem and permitted chromospheric emission lines of semiforbidden C II and Si II, Fe II, Fe I, Ni II, and Co II. Resolved profiles of the semiforbidden C II lines indicate a complex chromospheric turbulent velocity distribution with mean value of roughly 24 km/s, while their observed wavelengths indicate a 4 km/s downflow of the semiforbidden C II plasma. Twenty-five new emission lines have been found in the 2320-2370 A region, 17 of which have been identified with the aid of Skylab data obtained above the solar limb, including four lines from Co II (UV 8) and an Fe I (UV 12) line.

  16. Theory of {tau} mesonic decays

    SciTech Connect

    Li, B.A.

    1997-02-01

    Studies of {tau} mesonic decays are presented. A mechanism for the axial-vector current at low energies is proposed. The VMD is used to treat the vector current. All the meson vertices of both normal parity and abnormal parity (Wess-Zumino-Witten anomaly) are obtained from an effective chiral theory of mesons. a{sub 1} dominance is found in the decay modes of the {tau} lepton: 3{pi}, f(1285){pi}. Both the {rho} and the a{sub 1} meson contribute to the decay {tau}{r_arrow}K{sup {asterisk}}K{nu}; it is found that the vector current is dominant. CVC is tested by studying e{sup +}e{sup {minus}}{r_arrow}{pi}{sup +}{pi}{sup {minus}}. The branching ratios of {tau}{r_arrow}{omega}{pi}{nu} and K{bar K}{nu} are calculated. In terms of a similar mechanism the {Delta}s=1 decay modes of the {tau} lepton are studied and K{sub a} dominance is found in {tau}{r_arrow}K{sup {asterisk}}{pi}{nu} and K{sup {asterisk}}{eta}{nu}. The suppression of {tau}{r_arrow}K{rho}{nu} is revealed. The branching ratio of {tau}{r_arrow}{eta}K{nu} is computed. As a test of this theory, the form factors of {pi}{r_arrow}e{gamma}{nu} and K{r_arrow}e{gamma}{nu} are determined. The theoretical results agree with data reasonably well. {copyright} {ital 1997} {ital The American Physical Society}

  17. Closing the tau loop: the missing tau mutation

    PubMed Central

    McCarthy, Allan; Lonergan, Roisin; Olszewska, Diana A.; O’Dowd, Sean; Cummins, Gemma; Magennis, Brian; Fallon, Emer M.; Pender, Niall; Huey, Edward D.; Cosentino, Stephanie; O’Rourke, Killian; Kelly, Brendan D.; O’Connell, Martin; Delon, Isabelle; Farrell, Michael; Spillantini, Maria Grazia; Rowland, Lewis P.; Fahn, Stanley; Craig, Peter; Hutton, Michael

    2015-01-01

    Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5’ splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the ‘missing’ +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the ‘stem’ when the

  18. Closing the tau loop: the missing tau mutation.

    PubMed

    McCarthy, Allan; Lonergan, Roisin; Olszewska, Diana A; O'Dowd, Sean; Cummins, Gemma; Magennis, Brian; Fallon, Emer M; Pender, Niall; Huey, Edward D; Cosentino, Stephanie; O'Rourke, Killian; Kelly, Brendan D; O'Connell, Martin; Delon, Isabelle; Farrell, Michael; Spillantini, Maria Grazia; Rowland, Lewis P; Fahn, Stanley; Craig, Peter; Hutton, Michael; Lynch, Tim

    2015-10-01

    Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem

  19. The effects of estrogen, its antagonist ICI 182, 780, and interferon-tau on the expression of estrogen receptors and integrin alphaV beta 3 on cycle day 16 in bovine endometrium

    PubMed Central

    Kimmins, Sarah; Russell, Gerald L; Lim, Hai Choo; Hall, Brian K; MacLaren, Leslie A

    2003-01-01

    We have shown previously that downregulation of intercaruncular stromal integrin αvβ3 in bovine endometrium on day 16 of the estrous cycle coincided with the antibody recognition of estrogen receptors (ER) in the luminal epithelium. In pregnancy, these changes were not observed. Our hypothesis was that on day 16 of the estrous cycle, estrogen from the dominant follicle causes a reduction in integrin αvβ3 and affects ERα in the luminal epithelium. The pregnancy recognition protein, interferon-τ (IFN-τ), may prevent downregulation of integrin αvβ3 and suppress ERα expression in the luminal epithelium. On days 14 to 16, heifers received uterine infusions of the anti-estrogen ICI 182, 780, estradiol 17β, IFN-τ or the saline control. On day 16, reproductive tracts were collected for analysis of integrin αvβ3 and ERα. Estrogen receptor α immunoreactivity was largely restricted to the luminal epithelium in control animals. Using anti-ERα recognizing the amino terminus, estrogen-treated animals showed reactivity in the stroma, shallow and deep glands and myometrium as is typical of estrus, whereas ICI 182, 870 treated heifers showed little or no reactivity. In contrast, carboxyl terminus-directed antibodies showed a widespread distribution of ERα with reactivity detected in the uterine epithelium, stroma and myometrium of both estrogen and ICI 182, 780 treated animals. Heifers treated with IFN-τ had low ERα reactivity overall. Control and IFN-τ treated heifers had lower intercaruncular stromal expression of integrin αvβ3 in comparison to estrogen and ICI 182, 780 treatments. Overall, the results suggest that on day 16 of the estrous cycle, estrogen effects on integrin αvβ3 are indirect and do not directly involve ERα in the luminal epithelium. During pregnancy, interferon-tau may block ERα in the luminal epithelium but likely does not rescue integrin αvβ3 expression. PMID:12756058

  20. Interaction of Tau with Fe65 links tau to APP.

    PubMed

    Barbato, Christian; Canu, Nadia; Zambrano, Nicola; Serafino, Annalucia; Minopoli, Giuseppina; Ciotti, Maria Teresa; Amadoro, Giuseppina; Russo, Tommaso; Calissano, Pietro

    2005-03-01

    The beta-amyloid precursor protein APP and the microtubule-associated protein Tau play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the possible molecular events linking these two proteins are still unknown. Here, we show that Fe65, one of the ligands of the APP cytodomain, is associated with Tau in vivo and in vitro, as demonstrated by co-immunoprecipitation, co-localization, and FRET experiments. Deletion studies indicated that the N-terminal domain of Tau and the PTB1 domain of Fe65 are required for this association. This interaction is regulated by the phosphorylation of Tau at selected sites, by glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase 5 (Cdk5), and requires an intact microtubule network. Furthermore, laser scanner microscopy and co-immunoprecipitation experiments provide preliminary evidence of possible complex(es) involving Tau, Fe65, APP. These findings open new perspectives for the study of the possible crosstalk between these proteins in the pathogenesis of AD.

  1. Accelerated Human Mutant Tau Aggregation by Knocking Out Murine Tau in a Transgenic Mouse Model

    PubMed Central

    Ando, Kunie; Leroy, Karelle; Héraud, Céline; Yilmaz, Zehra; Authelet, Michèle; Suain, Valèrie; De Decker, Robert; Brion, Jean-Pierre

    2011-01-01

    Many models of human tauopathies have been generated in mice by expression of a human mutant tau with maintained expression of mouse endogenous tau. Because murine tau might interfere with the toxic effects of human mutant tau, we generated a model in which a pathogenic human tau protein is expressed in the absence of wild-type tau protein, with the aim of facilitating the study of the pathogenic role of the mutant tau and to reproduce more faithfully a human tauopathy. The Tg30 line is a tau transgenic mouse model overexpressing human 1N4R double-mutant tau (P301S and G272V) that develops Alzheimer's disease-like neurofibrillary tangles in an age-dependent manner. By crossing Tg30 mice with mice invalidated for their endogenous tau gene, we obtained Tg30xtau−/− mice that express only exogenous human double-mutant 1N4R tau. Although Tg30xtau−/− mice express less tau protein compared with Tg30, they exhibit signs of decreased survival, increased proportion of sarkosyl-insoluble tau in the brain and in the spinal cord, increased number of Gallyas-positive neurofibrillary tangles in the hippocampus, increased number of inclusions in the spinal cord, and a more severe motor phenotype. Deletion of murine tau accelerated tau aggregation during aging of this mutant tau transgenic model, suggesting that murine tau could interfere with the development of tau pathology in transgenic models of human tauopathies. PMID:21281813

  2. A Quantitative Analysis of Brain Soluble Tau and the Tau Secretion Factor.

    PubMed

    Han, Pengcheng; Serrano, Geidy; Beach, Thomas G; Caselli, Richard J; Yin, Junxiang; Zhuang, Ningning; Shi, Jiong

    2017-01-09

    Neurofibrillary tangles (NFTs) represent products of insoluble tau protein in the brains of patients with Alzheimer disease (AD). The cerebrospinal fluid (CSF) tau level is a biomarker in AD diagnosis. The soluble portion of tau protein in brain parenchyma is presumably the source for CSF tau but this has not previously been quantified. We measured CSF tau and soluble brain tau at autopsy in temporal and frontal brain tissue samples from 7 cognitive normal, 12 mild cognitively impaired, and 19 AD subjects. Based on the measured brain soluble tau, we calculated the whole brain tau load and estimated tau secretion factor. Our results suggest that the increase in NFT in AD is likely attributable to post-translational processes; the increase in CSF tau in AD patients is due to an accelerated carrier-based secretion. Moreover, cognitive dysfunction assessed by final Mini-Mental State Examination scores correlated with the secretion factor but not with the soluble tau.

  3. Elevated cerebrospinal fluid tau in Wernicke encephalopathy.

    PubMed

    Frijlink, Daphne W; Tilanus, Joachim J; Roks, Gerwin

    2012-08-08

    Wernicke encephalopathy (WE) commonly presents with oculomotor abnormalities, gait ataxia and confusion. WE can mimic rapidly progressive dementia syndromes, such as Creutzfeldt-Jakob disease (CJD). Cerebrospinal fluid (CSF) tau is frequently used for diagnosis of several dementia subtypes, predominantly CJD and Alzheimer's disease. The combination of very high CSF tau (tau) and normal phosphorylated tau (p-tau) levels is almost exclusively seen in aggressive diseases, such as CJD. The authors present a case of a woman with WE, caused by chronic insufficient dietary intake, with highly elevated CSF tau and normal p-tau. The clinical symptoms and CSF findings raised the suspicion of CJD. However, shortly after immediate treatment with thiamine the patient clinically improved. At follow-up, 2.5 months later, she had made a good recovery. This case of rapidly progressive dementia illustrates that, even in the case of a highly elevated CSF tau, clinicians should be alert for treatable causes such as WE.

  4. The. tau. -lepton and its associated neutrino

    SciTech Connect

    Pich, A. )

    1990-10-10

    This paper discusses the {tau}-lepton and the prospects for future improvements. It is shown how a better understanding of the {tau} properties could be used for testing fundamental aspects of the electroweak and strong interactions.

  5. Characterization of a Unique Undergraduate Multidisciplinary STEM K-5 Teacher Preparation Program

    ERIC Educational Resources Information Center

    O'Brien, Steve

    2010-01-01

    The K-5 school years are crucial, setting the framework for all subjects as well as critical thinking skills. The single most important component in a classroom is the teacher. However, in a formative timeframe for elementary-school aged children, the number of K-5 teachers that are educated with a Science, Technology, Engineering or Math…

  6. Segregation of Alloying Components of Steels R6M5K5 and R6M5K5-MP and its Relation with their Structure and Properties

    NASA Astrophysics Data System (ADS)

    Kremnev, L. S.; Sapronov, I. Yu.

    2014-03-01

    The distribution of alloying components in local regions of the martensitic matrix of high-speed steels R6M5K5 and R6M5K5-MP produced by the conventional process and by the method of powder metallurgy is studied. It is shown that the alloying components are segregated in the martensite, and the segregation is related to the content of retained austenite after hardening and to the microhardness and heat resistance of the steels after final heat treatment.

  7. Congeneric and (Essentially) Tau-Equivalent Estimates of Score Reliability: What They Are and How to Use Them

    ERIC Educational Resources Information Center

    Graham, James M.

    2006-01-01

    Coefficient alpha, the most commonly used estimate of internal consistency, is often considered a lower bound estimate of reliability, though the extent of its underestimation is not typically known. Many researchers are unaware that coefficient alpha is based on the essentially tau-equivalent measurement model. It is the violation of the…

  8. Tau Decays at BaBar

    SciTech Connect

    Hast, Carsten; /SLAC

    2009-01-22

    Recent results of tau lepton decay studies based on luminosities between 350 fb{sup -1} and 469 fb{sup -1} collected with the BABAR detector at the PEP-II e{sup +}e{sup -} collider at the SLAC National Accelerator Laboratory are presented. The analyses reported here are Charged Current Lepton Universality and measurements of |V{sub us}| using {tau}{sup -} {yields} e{sup -}{bar {nu}}{sub e}{nu}{sub {tau}}, {mu}{sup -}{bar {nu}}{sub {mu}}{nu}{sub {tau}}, {pi}{sup -} {nu}{sub {tau}}, and K{sup -}{nu}{sub {tau}} decays, as well as searches for Second Class Currents in {tau}{sup -} {yields} {omega}{pi}{sup -}{nu}{sub {tau}} decays, studies of Lepton Flavor Violations, and a tau mass measurement and CPT-Test. If not explicitly mentioned, charge conjugate decay modes are also implied. decays, as well as searches for Second Class Currents in {tau}{sup -} {yields} {omega}{pi}{sup -}{nu}{sub {tau}} decays, studies of Lepton Flavor Violations, and a tau mass measurement and CPT-Test. If not explicitly mentioned, charge conjugate decay modes are also implied.

  9. A Tau-Charm Factory at CEBAF

    SciTech Connect

    Seth, K.K.

    1994-04-01

    It is proposed that a Tau Charm Factory represents a natural extension of CEBAF into higher energy domains. The exciting nature of the physics of charm quarks and tau leptons is briefly reviewed and it is suggested that the concept of a linac-ring collider as a Tau Charm Factory at CEBAF should be seriously studied.

  10. Tau Trigger at the ATLAS Experiment

    SciTech Connect

    Benslama, K.; Kalinowski, A.; Belanger-Champange, C.; Brenner, R.; Bosman, M.; Casado, P.; Osuna, C.; Perez, E.; Vorwerk, V.; Czyczula, Z.; Dam, M.; Xella, S.; Demers, S.; Farrington, S.; Igonkina, O.; Kanaya, N.; Tsuno, S.; Ptacek, E.; Reinsch, A.; Strom, David M.; Torrence, E.; /Oregon U. /Sydney U. /Lancaster U. /Birmingham U.

    2011-11-09

    Many theoretical models, like the Standard Model or SUSY at large tan({beta}), predict Higgs bosons or new particles which decay more abundantly to final states including tau leptons than to other leptons. At the energy scale of the LHC, the identification of tau leptons, in particular in the hadronic decay mode, will be a challenging task due to an overwhelming QCD background which gives rise to jets of particles that can be hard to distinguish from hadronic tau decays. Equipped with excellent tracking and calorimetry, the ATLAS experiment has developed tau identification tools capable of working at the trigger level. This contribution presents tau trigger algorithms which exploit the main features of hadronic tau decays and describes the current tau trigger commissioning activities. Many of the SM processes being investigated at ATLAS, as well as numerous BSM searches, contain tau leptons in their final states. Being able to trigger effectively on the tau leptons in these events will contribute to the success of the ATLAS experiment. The tau trigger algorithms and monitoring infrastructure are ready for the first data, and are being tested with the data collected with cosmic muons. The development of efficiency measurements methods using QCD and Z {yields} {tau}{tau} events is well advanced.

  11. Prospect for measuring the CP phase in the $h\\tau\\tau$ coupling at the LHC

    SciTech Connect

    Askew, Andrew; Jaiswal, Prerit; Okui, Takemichi; Prosper, Harrison B.; Sato, Nobuo

    2015-04-01

    The search for a new source of CP violation is one of the most important endeavors in particle physics. A particularly interesting way to perform this search is to probe the CP phase in the $h\\tau\\tau$ coupling, as the phase is currently completely unconstrained by all existing data. Recently, a novel variable $\\Theta$ was proposed for measuring the CP phase in the $h\\tau\\tau$ coupling through the $\\tau^\\pm \\to \\pi^\\pm \\pi^0 \

  12. Evidence for B+ --> tau+ nu_tau Decays using Hadronic B Tags

    SciTech Connect

    del Amo Sanchez, P.; Lees, J.P.; Poireau, V.; Prencipe, E.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Milanes, D.A.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Brown, D.N.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; Osipenkov, I.L.; Koch, H.; Schroeder, T.; /Ruhr U., Bochum /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /Indian Inst. Tech., Guwahati /Harvard U. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa State U. /Iowa State U. /Johns Hopkins U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT /McGill U. /INFN, Milan /Milan U. /INFN, Milan /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /INFN, Naples /Naples U. /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Padua /Padua U. /INFN, Padua /INFN, Padua /Padua U. /Paris U., VI-VII /INFN, Perugia /Perugia U. /INFN, Pisa /Pisa U. /INFN, Pisa /Pisa, Scuola Normale Superiore /INFN, Pisa /Pisa U. /INFN, Pisa /Princeton U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /Rostock U. /Rutherford /DAPNIA, Saclay /SLAC /South Carolina U. /Southern Methodist U. /Stanford U., Phys. Dept. /SUNY, Albany /Tel Aviv U. /Tennessee U. /Texas U. /Texas U., Dallas /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /Valencia U. /Victoria U. /Warwick U. /Wisconsin U., Madison

    2011-08-11

    We present a search for the decay B{sup +} --> {tau}{sup +} {nu}{sub {tau}} using 467.8 x 10{sup 6} B{anti B} pairs collected at the {Upsilon}(4S) resonance with the BABAR detector at the SLAC PEP-II B-Factory. We select a sample of events with on completely reconstructed B{sup -} in an hadronic decay mode (B{sup -} --> D{sup (*)0}X{sup -} and B{sup -} --> J/{psi} X{sup -}). We examine the rest of the event to search for a B{sup +} --> {tau}{sup +} {nu}{sub {tau}} decay. We identify the {tau}{sup +} lepton in the following modes: {tau}{sup +} --> e{sup +} {nu}{sub e}{anti {nu}}{sub {tau}}, {tau}{sup +} --> {mu}{sup +} {nu}{sub {mu}}{anti {nu}}{sub {tau}}, {tau}{sup +} --> {pi}{sup +}{anti {nu}}{sub {tau}} and {tau}{sup +} --> {rho}{anti {nu}}{sub {tau}}. We find an excess of events with respect to expected background, which excludes the null signal hypothesis at the level of 3.3 {sigma} and can be converted to a branching fraction central value of B(B{sup +} --> {tau}{sup +} {nu}{sub {tau}})= (1.80{sup + 0.57}{sub - 0.54}(stat.) {+-} 0.26 (syst.)) x 10{sup -4}.

  13. Tau-66: evidence for a novel tau conformation in Alzheimer's disease.

    PubMed

    Ghoshal, N; García-Sierra, F; Fu, Y; Beckett, L A; Mufson, E J; Kuret, J; Berry, R W; Binder, L I

    2001-06-01

    We have characterized a novel monoclonal antibody, Tau-66, raised against recombinant human tau. Immunohistochemistry using Tau-66 reveals a somatic-neuronal stain in the superior temporal gyrus (STG) that is more intense in Alzheimer's disease (AD) brain than in normal brain. In hippocampus, Tau-66 yields a pattern similar to STG, except that neurofibrillary lesions are preferentially stained if present. In mild AD cases, Tau-66 stains plaques lacking obvious dystrophic neurites (termed herein 'diffuse reticulated plaques') in STG and the hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis reveals that Tau-66 is specific for tau, as there is no cross-reactivity with MAP2, tubulin, Abeta(1-40), or Abeta(1-42), although Tau-66 fails to react with tau or any other polypeptide on western blots. The epitope of Tau-66, as assessed by ELISA testing of tau deletion mutants, appears discontinuous, requiring residues 155-244 and 305-314. Tau-66 reactivity exhibits buffer and temperature sensitivity in an ELISA format and is readily abolished by SDS treatment. Taken together these lines of evidence indicate that the Tau-66 epitope is conformation-dependent, perhaps involving a close interaction of the proline-rich and the third microtubule-binding regions. This is the first indication that tau can undergo this novel folding event and that this conformation of tau is involved in AD pathology.

  14. New results on the tau lepton

    SciTech Connect

    Gan, K.K.

    1987-11-01

    This is a review of new results on the tau lepton. The results include precise measurements of the lifetime, measurements of the decay tau/sup -/ ..-->.. ..pi../sup -/2..pi../sup 0/nu/sub tau/ with much improved precision, and limits on decay modes containing eta mesons, including the second-class-current decay tau/sup -/ ..-->.. ..pi../sup -/eta nu/sub tau/. The implications of these new results on the discrepancy in the one-charged-particle decay modes are discussed. 52 refs., 6 figs., 2 tabs.

  15. Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer

    PubMed Central

    Wang, Oliver H.; Azizian, Nancy; Guo, Ming; Capello, Michela; Deng, Defeng; Zang, Fenglin; Fry, Jason; Katz, Matthew H.; Fleming, Jason B.; Lee, Jeffrey E.; Wolff, Robert A.; Hanash, Samir; Wang, Huamin; Maitra, Anirban

    2016-01-01

    Objectives MAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC). Materials and Methods The expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution. The RNA sequencing data of 112 PDAC patients were downloaded from the TCGA data portal. Immunoblotting and RNA sequencing analysis were used to examine the expression of MAP4K5 and E-cadherin in pancreatic cancer cell lines. The effect of knockdown MAP4K5 using siRNA on the expression of CDH1 and vimentin were examined by Real-time RT-PCR in Panc-1 and AsPC-1 cells. Statistical analyses were performed using IBM SPSS Statistics. Results MAP4K5 protein is expressed at high levels specifically in the pancreatic ductal cells of 100% non-neoplastic pancreas samples, but is decreased or lost in 77.1% (81/105) of PDAC samples. MAP4K5-low correlated with the loss of E-cadherin (P = 0.001) and reduced CES2 expression (P = 0.002) in our patient populations. The expression levels of MAP4K5 mRNA directly correlated with the expression levels of CDH1 mRNA (R = 0.2490, P = 0.008) in the second cohort of 112 PDAC patients from The Cancer Genome Atlas (TCGA) RNA-seq dataset. Similar correlations between the expression of MAP4K5 and E-cadherin were observed both at protein and mRNA levels in multiple pancreatic cancer cell lines. Knockdown MAP4K5 led to decreased CDH1 mRNA expression in Panc-1 and AsPC-1 cells. MAP4K5-low correlated significantly with reduced overall survival and was an independent prognosticator in patients with stage II PDAC. Conclusions MAP4K5 expression is decreased or lost in

  16. Secretion of full-length tau or tau fragments in a cell culture model.

    PubMed

    Pérez, Mar; Cuadros, Raquel; Hernández, Félix; Avila, Jesús

    2016-11-10

    Tau is a microtubule-associated protein that plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Several studies have suggested that tau may be secreted to extracellular medium and may be responsible of spreading of neurodegeneration. The overexpression of tau in cultured non-neuronal cells leads to the secretion of this protein. The proline-rich region of tau may serve as a membrane-binding site during the secretion of the full-length tau molecule. Tau fragments lacking this proline-region are either not secreted or are secreted in a distinct manner to the full-length molecule.

  17. Tau as a biomarker of neurodegenerative diseases

    PubMed Central

    Schraen-Maschke, Susanna; Sergeant, Nicolas; Dhaenens, Claire-Marie; Bombois, Stephanie; Deramecourt, Vincent; Caillet-Boudin, Marie-Laure; Pasquier, Florence; Maurage, Claude-Alain; Sablonniere, Bernard; Vanmechelen, Eugeen; Buee, Luc

    2008-01-01

    Summary The microtubule associated protein Tau is mainly expressed in neurons of the central nervous system and is crucial in axonal maintenance and axonal transport. The rationale for Tau as a biomarker of neurodegenerative diseases is that it is a major component of abnormal intraneuronal aggregates observed in numerous of these diseases named Tauopathies, including Alzheimer’s disease. The molecular diversity of Tau is very useful when analysing it in the brain or in the peripheral fluids. Immunohistochemical and biochemical characterisation of Tau aggregates in the brain allows the post-mortem classification and differential diagnosis of Tauopathies. As peripheral biomarker of Alzheimer’s disease in the cerebrospinal fluid, Tau proteins are now validated for diagnosis and predictive purposes. For the future, the detailed characterization of Tau in brain and in peripheral fluids will lead to novel promising biomarkers for differential diagnosis of dementia and monitoring of therapeutics. PMID:20477391

  18. Tau Protein and Adult Hippocampal Neurogenesis

    PubMed Central

    Fuster-Matanzo, Almudena; Llorens-Martín, María; Jurado-Arjona, Jerónimo; Avila, Jesús; Hernández, Félix

    2012-01-01

    Tau protein is a microtubule-associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10) and by presence of hyperphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis. PMID:22787440

  19. Tau appearance in atmospheric neutrino interactions

    SciTech Connect

    Hall, Lawrence J.; Murayama, Hitoshi

    1998-10-24

    If the correct interpretation of the Super-Kamiokande atmospheric neutrino data is {nu}{sub {mu}} {yields} {nu}{sub {tau}} oscillation, the contained data sample should already have more than 10 {tau} appearance events. We study the challenging task of detecting the {tau}, focusing on the decay chain {tau}{sup {+-}} {yields} {rho}{sup {+-}} {yields} {pi}{sup {+-}}{pi}{sup 0} in events with quasi-elastic {tau} production. The background level, which is currently quite uncertain because of a lack of relevant neutral current data, can be measured by the near detector in the K2K experiment. Our estimates of the background suggest that it may be possible to detect {tau} appearance in Super-Kamiokande with 5-10 years of running.

  20. Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption

    PubMed Central

    Jones, Emmalee M.; Dubey, Manish; Camp, Phillip J.; Vernon, Briana C.; Biernat, Jacek; Mandelkow, Eckhard; Majewski, Jaroslaw; Chi, Eva Y.

    2012-01-01

    The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's disease. However, the mechanisms of tau aggregation and toxicity remain unknown. Recent work has shown that lipid membrane can induce tau aggregation and that membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity, suggesting that the plasma membrane may play dual roles in tau pathology. This prompted our investigation to assess tau's propensity to interact with membranes and to elucidate the mutually disruptive structural perturbations the interactions induce in both tau and the membrane. We show that although highly charged and soluble, the full-length tau (hTau40) is also highly surface active, selectively inserts into anionic DMPG lipid monolayers and induces membrane morphological changes. To resolve molecular-scale structural details of hTau40 associated with lipid membranes, X-ray and neutron scattering techniques are utilized. X-ray reflectivity indicates hTau40's presence underneath a DMPG monolayer and penetration into the lipid headgroups and tailgroups, whereas grazing incidence X-ray diffraction shows that hTau40 insertion disrupts lipid packing. Moreover, both air/water and DMPG lipid membrane interfaces induce the disordered hTau40 to partially adopt a more compact conformation with density similar to that of a folded protein. Neutron reflectivity shows that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact. Our results show that hTau40's strong interaction with anionic lipids induces tau structural compaction and membrane disruption, suggesting possible membrane-based mechanisms of tau aggregation and toxicity in neurodegenerative diseases. PMID:22401494

  1. Formation and Propagation of Tau Oligomeric Seeds

    PubMed Central

    Gerson, Julia E.; Kayed, Rakez

    2013-01-01

    Tau misfolding and aggregation leads to the formation of neurofibrillary tangles (NFTs), which have long been considered one of the main pathological hallmarks for numerous neurodegenerative diseases known as tauopathies, including Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). However, recent studies completed both in vitro and in vivo suggest that intermediate forms of tau, known as tau oligomers, between the monomeric form and NFTs are the true toxic species in disease and the best targets for anti-tau therapies. However, the exact mechanism by which the spread of pathology occurs is unknown. Evidence suggests that tau oligomers may act as templates for the misfolding of native tau, thereby seeding the spread of the toxic forms of the protein. Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas. While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane. Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies. PMID:23882255

  2. Tau regulates the subcellular localization of calmodulin

    SciTech Connect

    Barreda, Elena Gomez de

    2011-05-13

    Highlights: {yields} In this work we have tried to explain how a cytoplasmic protein could regulate a cell nuclear function. We have tested the role of a cytoplasmic protein (tau) in regulating the expression of calbindin gene. We found that calmodulin, a tau-binding protein with nuclear and cytoplasmic localization, increases its nuclear localization in the absence of tau. Since nuclear calmodulin regulates calbindin expression, a decrease in nuclear calmodulin, due to the presence of tau that retains it at the cytoplasm, results in a change in calbindin expression. -- Abstract: Lack of tau expression in neuronal cells results in a change in the expression of few genes. However, little is known about how tau regulates gene expression. Here we show that the presence of tau could alter the subcellular localization of calmodulin, a protein that could be located at the cytoplasm or in the nucleus. Nuclear calmodulin binds to co-transcription factors, regulating the expression of genes like calbindin. In this work, we have found that in neurons containing tau, a higher proportion of calmodulin is present in the cytoplasm compared with neurons lacking tau and that an increase in cytoplasmic calmodulin correlates with a higher expression of calbindin.

  3. Workshop on Precision Measurements of $\\alpha_s$

    SciTech Connect

    Bethke, Siegfried; Hoang, Andre H.; Kluth, Stefan; Schieck, Jochen; Stewart, Iain W.; Aoki, S.; Beneke, M.; Bethke, S.; Blumlein, J.; Brambilla, N.; Brodsky, S.; /MIT, LNS

    2011-10-01

    These are the proceedings of the Workshop on Precision Measurements of {alpha}{sub s} held at the Max-Planck-Institute for Physics, Munich, February 9-11, 2011. The workshop explored in depth the determination of {alpha}{sub s}(m{sub Z}) in the {ovr MS} scheme from the key categories where high precision measurements are currently being made, including DIS and global PDF fits, {tau}-decays, electro-weak precision observables and Z-decays, event-shapes, and lattice QCD. These proceedings contain a short summary contribution from the speakers, as well as the lists of authors, conveners, participants, and talks.

  4. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.

    PubMed

    Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N; Jiang, Shanya; Cardona, Astrid; Ransohoff, Richard M; Lamb, Bruce T; Bhaskar, Kiran

    2015-06-01

    Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.

  5. Selected Topics in Tau Physics from BaBar

    SciTech Connect

    Paramesvaran, S.; /Royal Holloway, U. of London

    2012-04-06

    Selected results from {tau} analyses performed using the BABAR detector at the SLAC National Accelerator Laboratory are presented. A precise measurement of the {tau} mass and the {tau}{sup +}{tau}{sup -} mass difference is undertaken using the hadronic decay mode {tau}{sup {+-}} {yields} {pi}{sup +}{pi}{sup -}{pi}{sup {+-}}{nu}{sub {tau}}. In addition an investigation into the strange decay modes {tau}{sup -} {yields} K{sub S}{sup 0}{pi}{sup -}{pi}{sup 0}{nu}{sub {tau}} and {tau}{sup -} {yields} K{sub S}{sup 0}{pi}{sup -}{nu}{sub {tau}} is also presented, including a fit to the {tau}{sup -} {yields} K{sub S}{sup 0}{pi}{sup -}{nu}{sub {tau}} invariant mass spectrum. Precise values for M(K*(892)) and {Lambda}(K*(892)) are obtained.

  6. The Search for B+ to Tau+ Nu(Tau) at BaBar

    SciTech Connect

    Corwin, L.A.; /SLAC

    2007-01-08

    We present a search for the decay B{sup +} {yields} {tau}{sup +}{nu}{sub {tau}} using 288 fb{sup -1} of data collected at the {Upsilon}(4S) resonance with the BABAR detector at the SLAC PEP-II B-Factory. A sample of events with one reconstructed semileptonic B decay (B{sup -} {yields} D{sup o}{ell}{sup -}{bar {nu}}{sub {ell}}X) is selected, and in the recoil a search for B{sup +} {yields} {tau}{sup +}{nu}{sub {tau}} signal is performed. The {tau} is identified in the following channels: {tau}{sup +} {yields} e{sup +}{nu}{sub e}{bar {nu}}{sub {tau}}, {tau}{sup +} {yields} {mu}{sup +} {nu}{sub {mu}}{bar {nu}}{sub {tau}}, {tau}{sup +} {yields} {pi}{sup +}{pi}{sup 0}{bar {nu}}{sub {tau}}. We measure a branching fraction of {Beta}(B{sup +} {yields} {tau}{sup +}{nu}{sub {tau}}) = 0.88{sub -0.67}{sup +0.68}(stat.) {+-} 0.11(syst.) x 10{sup -4} and extract an upper limit on the branching fraction, at the 90% confidence level, of {Beta}(B{sup +} {yields} {tau}{sup +}{nu}{sub {tau}}) < 1.8 x 10{sup -4}. We calculate the product of the B meson decay constant and |V{sub ub}| to be f{sub B} {center_dot} |V{sub ub}| = (7.0{sub -3.6}{sup +2.3}(stat.){sub -0.5}{sup +0.4}(syst.)) x 10{sup -4} GeV.

  7. Prospect for measuring the CP phase in the $$h\\tau\\tau$$ coupling at the LHC

    DOE PAGES

    Askew, Andrew; Jaiswal, Prerit; Okui, Takemichi; ...

    2015-04-01

    The search for a new source of CP violation is one of the most important endeavors in particle physics. A particularly interesting way to perform this search is to probe the CP phase in themore » $$h\\tau\\tau$$ coupling, as the phase is currently completely unconstrained by all existing data. Recently, a novel variable $$\\Theta$$ was proposed for measuring the CP phase in the $$h\\tau\\tau$$ coupling through the $$\\tau^\\pm \\to \\pi^\\pm \\pi^0 \

  8. Measurement of the Semileptonic Decays B->D tau nu and B->D* tau nu

    SciTech Connect

    Aubert, : B.

    2009-02-23

    The authors present measurements of the semileptonic decays B{sup -} {yields} D{sup 0} {tau}{sup -} {bar {nu}}{sub {tau}}, B{sup -} {yields} D*{sup 0} {tau}{sup -}{bar {nu}}{sub {tau}}, {bar B}{sup 0} {yields} D{sup +} {tau}{sup -} {bar {nu}}{sub {tau}}, and {bar B}{sup 0} {yields} D*{sup +} {tau}{sup -}{bar {nu}}{sub {tau}}, which are sensitive to non-Standard Model amplitudes in certain scenarios. The data sample consists of 232 x 10{sup 6} {Upsilon}(4S) {yields} B{bar B} decays collected with the BABAR detector at the PEP-II e{sup +}e{sup -} collider. They select events with a D or D* meson and a light lepton ({ell} = e or {mu}) recoiling against a fully reconstructed B meson. They perform a fit to the joint distribution of lepton momentum and missing mass squared to distinguish signal B {yields} D{sup (*)}{tau}{sup -} {bar {nu}}{sub {tau}} ({tau}{sup -} {yields} {ell}{sup -} {bar {nu}}{sub {ell}}{nu}{sub {tau}}) events from the backgrounds, predominantly B {yields} D{sup (*)} {ell}{sup -}{bar {nu}}{sub {ell}}. They measure the branching-fraction ratios R(D) {triple_bond} {Beta}(B {yields} D{tau}{sup -} {bar {nu}}{sub {tau}})/{Beta}(B {yields} D{ell}{sup -} {bar {nu}}{sub {ell}}) and R(D*) {triple_bond} {Beta}(B {yields} D*{tau}{sup -} {bar {nu}}{sub {tau}})/{Beta}(B {yields} D* {ell}{sup -} {bar {nu}}{sub {ell}}) and, from a combined fit to B{sup -} and {bar B}{sup 0} channels, obtain the results R(D) = (41.6 {+-} 11.7 {+-} 5.2)% and R(D*) = (29.7 {+-} 5.6 {+-} 1.8)%, where the uncertainties are statistical and systematic. Normalizing to measured B{sup -} {yields} D{sup (*)0} {ell}{sup -} {bar {nu}}{sub {ell}} branching fractions, they obtain {Beta}(B {yields} D{tau}{sup -} {bar {nu}}{sub {tau}}) = (0.86 {+-} 0.24 {+-} 0.11 {+-} 0.06)% and {Beta}(B {yields} D*{tau}{sup -} {bar {nu}}{sub {tau}}) = (1.62 {+-} 0.31 {+-} 0.10 {+-} 0.05)%, where the additional third uncertainty is from the normalization mode. They also present, for the first time, distributions of

  9. Exclusive branching-fraction measurements of semileptonic tau decays into three charged hadrons, into phipi(-)nu tau, and into phi K(-)nu tau.

    PubMed

    Aubert, B; Bona, M; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Gill, M S; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Pegna, D Lopes; Lynch, G; Mir, L M; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; del Amo Sanchez, P; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Watson, A T; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Cottingham, W N; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Sherwood, D J; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Best, D S; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Roethel, W; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; Hadavand, H K; Hill, E J; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Cheng, C H; Dvoretskii, A; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Zeng, Q; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Brandt, T; Klose, V; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Lee, C L; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Nash, J A; Nikolich, M B; Vazquez, W Panduro; Behera, P K; Chai, X; Charles, M J; Mallik, U; Meyer, N T; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gritsan, A V; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Oyanguren, A; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; Clarke, C K; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Jackson, P S; McMahon, T R; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; Naisbit, M T; Williams, J C; Yi, J I; Chen, C; Hulsbergen, W D; Jawahery, A; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Saremi, S; Staengle, H; Cowan, R; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; Cavallo, N; De Nardo, G; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; LoSecco, J M; Benelli, G; Corwin, L A; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Rahimi, A M; Regensburger, J J; Ter-Antonyan, R; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Potter, C T; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Hartfiel, B L; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Gladney, L; Biasini, M; Covarelli, R; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Cenci, R; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Judd, D; Wagoner, D E; Biesiada, J; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Gioi, L Li; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Tehrani, F Safai; Voena, C; Ebert, M; Schröder, H; Waldi, R; Adye, T; Franek, B; Olaiya, E O; Ricciardi, S; Wilson, F F; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; de Monchenault, G Hamel; Kozanecki, W; Legendre, M; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dujmic, D; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Wagner, A P; Weaver, M; Weinstein, A J R; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Satpathy, A; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Pappagallo, M; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Flood, K T; Hollar, J J; Kutter, P E; Mellado, B; Mihalyi, A; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Yu, Z; Neal, H

    2008-01-11

    Using a data sample corresponding to an integrated luminosity of 342 fb(-1) collected with the BABAR detector at the SLAC PEP-II electron-positron storage ring operating at a center-of-mass energy near 10.58 GeV, we measure B(tau(-)--> pi(-)pi(-)pi+nu(tau)(ex.K(S0))=(8.83+/-0.01+/-0.13)%, B(tau(-) -->K(-)pi(-)pi+nu tau(ex.K(S0))=(0.273+/-0.002+/-0.009)%, B(tau(-) -->K(-)pi(-)K+nu tau)=(0.1346+/-0.0010+/-0.0036)%, and B(tau(-) -->K(-)K(-)K+nu tau)=(1.58+/-0.13+/-0.12)x10;{-5}, where the uncertainties are statistical and systematic, respectively. These include significant improvements over previous measurements and a first measurement of B(tau(-) -->K(-)K(-)K+nu tau) in which no resonance structure is assumed. We also report a first measurement of B(tau(-) -->var phi(-)nu tau)=(3.42+/-0.55+/-0.25)x10(-5), a new measurement of B(tau(-) -->var phi K(-)nu tau)=(3.39+/-0.20+/-0.28)x10(-5) and a first upper limit on B(tau(-) -->K(-)K(-)K+nu tau(ex.var phi)).

  10. Mobile Devices and the Teacher Perceived Barriers Impacting Effective Integration in the K-5 Classroom

    ERIC Educational Resources Information Center

    Nixon, Tina S.

    2013-01-01

    This qualitative, phenomenological study explored the teacher perceived barriers of using mobile devices in the K-5 classroom. Research confirms teachers face various types of variables and become reluctant to use technology within their curriculum driven lessons. This study sought to understand what teachers perceive as barriers, and how the…

  11. Science IDEAS: A Research-Based K-5 Interdisciplinary Instructional Model Linking Science and Literacy

    ERIC Educational Resources Information Center

    Romance, Nancy R.; Vitale, Michael R.

    2012-01-01

    Science IDEAS is an evidence-based model that reflects interdisciplinary research findings that support the integration of literacy (e.g., reading comprehension) within science instruction in grades K-5. Presented is a framework for planning integrated science and literacy instruction in which six elements (hands-on investigations, reading,…

  12. Democratic Bodies: Exemplary Practice and Democratic Education in a K-5 Dance Residency

    ERIC Educational Resources Information Center

    Leonard, Alison E.

    2014-01-01

    This research highlights a K-5 dance artist-in-residence as a form of democratic and exemplary dance education that ignited collaboration, promoted equity, fostered student autonomy, and demonstrated rigor in school curriculum. Through examining observation, interview, and performance-based data and calling upon critical, democratic education…

  13. K-5 Student Experiences in a Dance Residency: A Case Study

    ERIC Educational Resources Information Center

    Leonard, Alison E.; McShane-Hellenbrand, Karen

    2012-01-01

    In this article, the collaborating authors, a researcher and dance artist, confront assumptions surrounding dance's experiential nature and assessment in schools. Presenting findings from a qualitative case study assessment of a three-week, whole-school dance artist-in-residence at a diverse and inclusive metropolitan K-5 school, the authors focus…

  14. Stress Education Curriculum: Grades K-5, Elementary School Level. Fourth Edition.

    ERIC Educational Resources Information Center

    Trotter, Jennie C.

    Stress is an inevitable part of living, but too much stress can have damaging consequences. Ways in which children can respond positively to stress are covered in this curriculum guide. It was developed to help teachers teach students, grades K-5, ways to cope with stress. Its curriculum objectives include helping students understand stress and…

  15. Raising the Level of Cultural Awareness of K-5 Aged Students through Multicultural Arts Education.

    ERIC Educational Resources Information Center

    Sears, Laurie A.

    This practicum was designed to provide K-5 students with diverse cultural experiences through multicultural art education to develop cultural awareness. Community members, parents, museum docents, students, and staff pursued a year-long exploration into the diverse cultures of the world through the study, celebration, and sharing of heritages,…

  16. Perceptions of Stress among Native American and Hispanic K-5 Teachers

    ERIC Educational Resources Information Center

    Lotz-Drlik, Jane Elizabeth

    2012-01-01

    Within the context of a nationwide shortage of teachers of color, stable enrollment of Native American students, and increasing enrollments of Hispanic students, the purpose of this study was to examine self-reported stress among Native American, Hispanic, and Caucasian K-5 teachers. This was a mixed-methods study, with both quantitative and…

  17. Developing Learning Skills through Children's Literature: An Idea Book for K-5 Classrooms and Libraries.

    ERIC Educational Resources Information Center

    Laughlin, Mildred Knight; Watt, Letty S.

    Designed to be planned jointly by teachers and school library media specialists, the 60 units of study described in this book suggest ideas for sharing literature that may be used in developing a scope and sequence of literature experiences for children in grades K-5. For primary grades K-2, the activities are primarily arranged through sharing…

  18. New Features about Tau Function and Dysfunction

    PubMed Central

    Medina, Miguel; Hernández, Félix; Avila, Jesús

    2016-01-01

    Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future. PMID:27104579

  19. Physics with tau leptons at CDF

    SciTech Connect

    Hays, C.P.; /Oxford U.

    2007-04-01

    The {radical}s = 1.96 TeV p{bar p} collisions produced by the Tevatron result in many processes with tau leptons in the final state. The CDF Collaboration has studied these final states in Z and t{bar t} production, and has used tau leptons to search for evidence of Higgs, sparticle, and Z{prime} production.

  20. Tau phosphorylation affects its axonal transport and degradation

    PubMed Central

    Rodríguez-Martín, Teresa; Cuchillo-Ibáñez, Inmaculada; Noble, Wendy; Nyenya, Fanon; Anderton, Brian H.; Hanger, Diane P.

    2013-01-01

    Phosphorylated forms of microtubule-associated protein tau accumulate in neurofibrillary tangles in Alzheimer's disease. To investigate the effects of specific phosphorylated tau residues on its function, wild type or phosphomutant tau was expressed in cells. Elevated tau phosphorylation decreased its microtubule binding and bundling, and increased the number of motile tau particles, without affecting axonal transport kinetics. In contrast, reducing tau phosphorylation enhanced the amount of tau bound to microtubules and inhibited axonal transport of tau. To determine whether differential tau clearance is responsible for the increase in phosphomimic tau, we inhibited autophagy in neurons which resulted in a 3-fold accumulation of phosphomimic tau compared with wild type tau, and endogenous tau was unaffected. In autophagy-deficient mouse embryonic fibroblasts, but not in neurons, proteasomal degradation of phosphomutant tau was also reduced compared with wild type tau. Therefore, autophagic and proteasomal pathways are involved in tau degradation, with autophagy appearing to be the primary route for clearing phosphorylated tau in neurons. Defective autophagy might contribute to the accumulaton of tau in neurodegenerative diseases. PMID:23601672

  1. Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

    PubMed

    Rodríguez-Martín, Teresa; Pooler, Amy M; Lau, Dawn H W; Mórotz, Gábor M; De Vos, Kurt J; Gilley, Jonathan; Coleman, Michael P; Hanger, Diane P

    2016-01-01

    Expression of the frontotemporal dementia-related tau mutation, P301L, at physiological levels in adult mouse brain (KI-P301L mice) results in overt hypophosphorylation of tau and age-dependent alterations in axonal mitochondrial transport in peripheral nerves. To determine the effects of P301L tau expression in the central nervous system, we examined the kinetics of mitochondrial axonal transport and tau phosphorylation in primary cortical neurons from P301L knock-in (KI-P301L) mice. We observed a significant 50% reduction in the number of mitochondria in the axons of cortical neurons cultured from KI-P301L mice compared to wild-type neurons. Expression of murine P301L tau did not change the speed, direction of travel or likelihood of movement of mitochondria. Notably, the angle that defines the orientation of the mitochondria in the axon, and the volume of individual moving mitochondria, were significantly increased in neurons expressing P301L tau. We found that murine tau phosphorylation in KI-P301L mouse neurons was diminished and the ability of P301L tau to bind to microtubules was also reduced compared to tau in wild-type neurons. The P301L mutation did not influence the ability of murine tau to associate with membranes in cortical neurons or in adult mouse brain. We conclude that P301L tau is associated with mitochondrial changes and causes an early reduction in murine tau phosphorylation in neurons coupled with impaired microtubule binding of tau. These results support the association of mutant tau with detrimental effects on mitochondria and will be of significance for the pathogenesis of tauopathies.

  2. Glycan Determinants of Heparin-Tau Interaction.

    PubMed

    Zhao, Jing; Huvent, Isabelle; Lippens, Guy; Eliezer, David; Zhang, Anqiang; Li, Quanhong; Tessier, Peter; Linhardt, Robert J; Zhang, Fuming; Wang, Chunyu

    2017-03-14

    Tau aggregates into paired helical filaments within neurons, a pathological hallmark of Alzheimer's disease. Heparin promotes tau aggregation and recently has been shown to be involved in the cellular uptake of tau aggregates. Although the tau-heparin interaction has been extensively studied, little is known about the glycan determinants of this interaction. Here, we used surface plasmon resonance (SPR) and NMR spectroscopy to characterize the interaction between two tau fragments, K18 and K19, and several polysaccharides, including heparin, heparin oligosaccharides, chemically modified heparin, and related glycans. Using a heparin-immobilized chip, SPR revealed that tau K18 and K19 bind heparin with a KD of 0.2 and 70 μM, respectively. In SPR competition experiments, N-desulfation and 2-O-desulfation had no effect on heparin binding to K18, whereas 6-O-desulfation severely reduced binding, suggesting a critical role for 6-O-sulfation in the tau-heparin interaction. The tau-heparin interaction became stronger with longer-chain heparin oligosaccharides. As expected for an electrostatics-driven interaction, a moderate amount of salt (0.3 M NaCl) abolished binding. NMR showed the largest chemical-shift perturbation (CSP) in R2 in tau K18, which was absent in K19, revealing differential binding sites in K18 and K19 to heparin. Dermatan sulfate binding produced minimal CSP, whereas dermatan disulfate, with the additional 6-O-sulfo group, induced much larger CSP. 2-O-desulfated heparin induced much larger CSP in K18 than 6-O-desulfated heparin. Our data demonstrate a crucial role for the 6-O-sulfo group in the tau-heparin interaction, which to our knowledge has not been reported before.

  3. Combination of keratins and alpha-smooth muscle actin distinguishes secretory coils from ducts of eccrine sweat glands.

    PubMed

    Li, Haihong; Zhang, Xiang; Zeng, Shaopeng; Li, Xuexue; Zhang, Bingna; Chen, Lu; Lin, Changmin; Zhang, Mingjun; Tang, Shijie; Fu, Xiaobing

    2015-04-01

    Eccrine sweat glands are comprised of secretory coils and ducts, which are distinct in morphology and function. To better understand the roles of the two parts in development, homeostasis, wound repair and regeneration of eccrine sweat glands, we must distinguish between them. In this study, the localization of keratins and alpha-SMA in human eccrine sweat glands was examined by immunofluorescence staining. Based on the differential localization of keratins and alpha-SMA in different cell types, four pairs of antibodies (K5/K7, K5/alpha-SMA, K14/K7 and K14/alpha-SMA) were used to differentiate secretory coils from ducts by double-immunofluorescence staining. Immunofluorescence staining showed that myoepithelial cells of secretory coils expressed K5, K14 and alpha-SMA, whereas secretory cells of secretory coils expressed K7, K8, K15, K18 and K19. Ductal cells expressed K5, K8, K14 and K19. Double-staining showed that the secretory coils were K5(+)/K7(+), K5(+)/alpha-SMA(+), K14(+)/K7(+) and K14(+)/alpha-SMA(+), whereas ducts were K5(+)/K7(-), K5(+)/alpha-SMA(-), K14(+)/K7(-) and K14(+)/alpha-SMA(-). In conclusion, by combining use of keratins and alpha-SMA antibodies, secretory coils can be easily differentiated from ducts in morphology.

  4. A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy

    PubMed Central

    Trzeciakiewicz, Hanna; Tseng, Jui-Heng; Wander, Connor M.; Madden, Victoria; Tripathy, Ashutosh; Yuan, Chao-Xing; Cohen, Todd J.

    2017-01-01

    Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer’s disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential “two-hit” mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies. PMID:28287136

  5. Hadronic decays of the tau lepton : {tau}- {yields} ({pi}{pi}{pi})- {nu}{tau} within Resonance Chiral Theory

    SciTech Connect

    Gomez Dumm, D.; Pich, A.; Portoles, J.

    2006-01-12

    {tau} decays into hadrons foresee the study of the hadronization of vector and axial-vector QCD currents, yielding relevant information on the dynamics of the resonances entering into the processes. We analyse {tau} {yields} {pi}{pi}{pi}{nu}{tau} decays within the framework of the Resonance Chiral Theory, comparing this theoretical scheme with the experimental data, namely ALEPH spectral function and branching ratio. Hence we get values for the mass and on-shell width of the a 1 (1260) resonance, and provide the structure functions that have been measured by OPAL and CLEO-II.

  6. Polarized spectral properties of Tm 3+:K 5Bi(MoO 4) 4 crystal

    NASA Astrophysics Data System (ADS)

    Wu, Z. Q.; Tang, J. F.; Huang, J. H.; Gong, X. H.; Chen, Y. J.; Lin, Y. F.; Luo, Z. D.; Huang, Y. D.

    2011-11-01

    Trivalent thulium-doped K 5Bi(MoO 4) 4 single crystals were grown by the Czochralski method. Its polarized absorption and fluorescence spectra and fluorescence decay curves were recorded at room temperature. On the basis of the Judd-Ofelt theory, the spectral parameters of the Tm 3+:K 5Bi(MoO 4) 4 crystal were calculated. The cross relaxations between Tm 3+ ions were analyzed. The emission cross sections of the 3F 4 → 3H 6 transition were obtained by the Fuchtbauer-Ladenburg formula and then the gain cross sections around 1.9 μm were calculated. The peak emission cross section and width of emission band around 1.9 μm are comparable to those for Tm 3+:YAG and the tunable range is about 280 nm for the potential ˜1.9 μm laser operation via the 3F 4 → 3H 6 transition.

  7. E(k)∝ k-5 observed at large k for rapidly rotating turbulent flow*

    NASA Astrophysics Data System (ADS)

    Swinney, Harry L.; Jung, Sungwhan; Yarbrough, Ray

    2004-11-01

    We have made velocity measurements on a quasi-two-dimensional turbulent flow in a rapidly rotating annulus (Reynolds number 20000, Rossby number 0.03). Earlier measurements demonstrated that in the inverse cascade (low wavenumbers), the energy scaling is given by E(k)∝ k-2 rather than the expected E(k)∝ k-5/3 [1]. Extending the measurements to high wavenumbers (into the forward enstrophy cascade), we find E(k)∝ k-5 rather than the E(k)∝ k-3 that has been found for a non-rotating quasi-two-dimensional flow [2]. Our observed value of -5 for the exponent is the same as a recently predicted bound for the exponent [3]. *Supported by ONR [1] C. N. Baroud et al., Phys. Rev. Lett. 88, 114501 (2002). [2] J. Paret and P. Tabeling, Phys. Fluids 10, 3126 (1998). [3] C. V. Tran and J. Bowman, Phys. Rev. E 69, 036303 (2004).

  8. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.

    PubMed

    Iovino, Mariangela; Agathou, Sylvia; González-Rueda, Ana; Del Castillo Velasco-Herrera, Martin; Borroni, Barbara; Alberici, Antonella; Lynch, Timothy; O'Dowd, Sean; Geti, Imbisaat; Gaffney, Daniel; Vallier, Ludovic; Paulsen, Ole; Káradóttir, Ragnhildur Thóra; Spillantini, Maria Grazia

    2015-11-01

    Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.

  9. K5LaLi2F10:Er3+ crystals. Growth, structure and optical properties

    NASA Astrophysics Data System (ADS)

    Dominiak-Dzik, G.; Golab, S.; Baluka, M.; Pietraszko, A.; Hermanowicz, K.

    1999-07-01

    Single crystals of K5LaLi2F10:Er3+ and K5LaLi2F10 were synthesized and the structural determination was made by x-ray diffraction analysis. The structure is orthorhombic with space group Pnma. The unit cell parameters are: a = 20.775, b = 7.822 and c = 6.963 Å. The infrared transmission and Raman scattering spectra of oriented single crystals were measured and discussed in terms of factor group analysis and x-ray structure. A vibrational assignment is proposed. Preliminary optical properties of Er3+ ions in K5LaLi2F10 crystals have been investigated using absorption, luminescence and lifetime measurements in the 5-300 K temperature range. The low temperature absorption and luminescence spectra of Er3+ have allowed us to identify the Stark levels of low-lying multiplets. The luminescence observed at 5 K has been attributed to the 4S3/2icons/Journals/Common/to" ALT="to" ALIGN="TOP"/>4I15/2 (18 300 cm-1), 4F9/2icons/Journals/Common/to" ALT="to" ALIGN="TOP"/>4I15/2 (15 000 cm-1), 4S3/2icons/Journals/Common/to" ALT="to" ALIGN="TOP"/>4I13/2 (11800 cm-1) and 4I11/2icons/Journals/Common/to" ALT="to" ALIGN="TOP"/>4I15/2 (10000 cm-1) transitions. The lifetimes of selected excited states were measured at 5 and 300 K temperature. The obtained data gave the first insight into the luminescent properties of Er3+ ions in the fluorine surroundings in K5LaLi2F10 crystals.

  10. Common Core Literacy Lesson Plans: Ready-to-Use Resources, K-5

    ERIC Educational Resources Information Center

    Davis, Lauren

    2013-01-01

    Schools nationwide are transitioning to the Common Core--our advice to you: Don't go it alone! Our new book, "Common Core Literacy Lesson Plans: Ready-to-Use Resources, K-5," shows you that teaching the Common Core State Standards in the elementary grades doesn't have to be intimidating! This easy-to-use guide provides model lesson plans for…

  11. Coefficient alpha and interculture test selection.

    PubMed

    Thurber, Steven; Kishi, Yasuhiro

    2014-04-01

    The internal consistency reliability of a measure can be a focal point in an evaluation of the potential adequacy of an instrument for adaptation to another cultural setting. Cronbach's alpha (α) coefficient is often used as the statistical index for such a determination. However, alpha presumes a tau-equivalent test and may constitute an inaccurate population estimate for multidimensional tests. These notions are expanded and examined with a Japanese version of a questionnaire on nursing attitudes toward suicidal patients, originally constructed in Sweden using the English language. The English measure was reported to have acceptable internal consistency (α) albeit the dimensionality of the questionnaire was not addressed. The Japanese scale was found to lack tau-equivalence. An alternative to alpha, "composite reliability," was computed and found to be below acceptable standards in magnitude and precision. Implications for research application of the Japanese instrument are discussed.

  12. Probing M subdwarf metallicity with an esdK5+esdM5.5 binary

    NASA Astrophysics Data System (ADS)

    Pavlenko, Ya. V.; Zhang, Z. H.; Gálvez-Ortiz, M. C.; Kushniruk, I. O.; Jones, H. R. A.

    2015-10-01

    Context. We present a spectral analysis of the binary G 224-58 AB, which consists of the coolest M extreme subdwarf (esdM5.5) and a brighter primary (esdK5). This binary may serve as a benchmark for metallicity measurement calibrations and as a test bed for atmospheric and evolutionary models for esdM objects. Aims: We perform the analysis of optical and infrared spectra of both components to determine their parameters. Methods: We determine abundances primarily using high-resolution optical spectra of the primary. Other parameters were determined from the fits of synthetic spectra computed with these abundances to the observed spectra from 0.4 to 2.5 microns for both components. Results: We determine Teff = 4625 ± 100 K, log g = 4.5 ± 0.5 for the A component and Teff = 3200 ± 100 K, log g = 5.0 ± 0.5, for the B component. We obtained abundances of [ Mg / H ] = + - 1.51 ± 0.08, [Ca/H] = - 1.39 ± 0.03, [Ti/H] = - 1.37 ± 0.03 for alpha group elements and [CrH] = - 1.88 ± 0.07, [Mn/H] = - 1.96 ± 0.06, [ Fe / H ] = - 1.92 ± 0.02, [Ni/H] = - 1.81 ± 0.05 and [Ba/H] = - 1.87 ± 0.11 for iron group elements from fits to the spectral lines observed in the optical and infrared spectral regions of the primary. We find consistent abundances with fits to the secondary albeit at lower signal to noise. Conclusions: Abundances of different elements in G 224-58 A and G 224-58 B atmospheres cannot be described by one metallicity parameter. The offset of ˜0.4 dex between the abundances derived from alpha element and iron group elements corresponds with our expectation for metal-deficient stars. We thus clarify that some indices used to date to measure metallicities for establishing esdM stars, based on CaH, MgH, and TiO band system strength ratios in the optical and H2O in the infrared, relate to abundances of alpha-element group rather than to iron peak elements. For metal deficient M dwarfs with [ Fe / H ] < - 1.0, this provides a ready explanation for apparently

  13. NMR observation of Tau in Xenopus oocytes

    NASA Astrophysics Data System (ADS)

    Bodart, Jean-François; Wieruszeski, Jean-Michel; Amniai, Laziza; Leroy, Arnaud; Landrieu, Isabelle; Rousseau-Lescuyer, Arlette; Vilain, Jean-Pierre; Lippens, Guy

    2008-06-01

    The observation by NMR spectroscopy of microinjected 15N-labelled proteins into Xenopus laevis oocytes might open the way to link structural and cellular biology. We show here that embedding the oocytes into a 20% Ficoll solution maintains their structural integrity over extended periods of time, allowing for the detection of nearly physiological protein concentrations. We use these novel conditions to study the neuronal Tau protein inside the oocytes. Spectral reproducibility and careful comparison of the spectra of Tau before and after cell homogenization is presented. When injecting Tau protein into immature oocytes, we show that both its microtubule association and different phosphorylation events can be detected.

  14. Tensor mesons produced in tau lepton decays

    SciTech Connect

    Lopez Castro, G.; Munoz, J. H.

    2011-05-01

    Light tensor mesons (T=a{sub 2}, f{sub 2} and K{sub 2}*) can be produced in decays of {tau} leptons. In this paper we compute the branching ratios of {tau}{yields}T{pi}{nu} decays by assuming the dominance of intermediate virtual states to model the form factors involved in the relevant hadronic matrix elements. The exclusive f{sub 2}(1270){pi}{sup -} decay mode turns out to have the largest branching ratio, of O(10{sup -4}). Our results indicate that the contribution of tensor meson intermediate states to the three-pseudoscalar channels of {tau} decays are rather small.

  15. The role of the VQIVYK peptide in tau protein phosphorylation.

    PubMed

    Perez, Mar; Santa-María, Ismael; Tortosa, Elena; Cuadros, Raquel; Del Valle, Mercedes; Hernández, Felix; Moreno, Francisco J; Avila, Jesús

    2007-11-01

    Although it remains unclear whether they are related to one another, tau aggregation and phosphorylation are the main pathological hallmarks of the neuronal disorders known as tauopathies. The capacity to aggregate is impaired in a variant of the tau 3R isoform that lacks residues 306-311 (nomenclature for the largest CNS tau isoform) and hence, we have taken advantage of this feature to study how phosphorylation and aggregation may be related as well as the role of this six amino acid peptide (VQIVYK). Through these analyses, we found that the phosphorylation of the tau variant was higher than that of the complete tau protein and that not only the deletion of these residues, but also the interaction of these residues, in tau 3R, with thioflavin-S augmented tau phosphorylation by glycogen synthase kinase 3. In addition, the binding of the peptide containing the residues 306-311 to the whole tau protein provoked an increase in tau phosphorylation. This observation could be physiologically relevant as may suggest that tau-tau interactions, through those residues, facilitate tau phosphorylation. In summary, our data indicate that deletion of residues VQIVYK, in tau protein produces an increase in tau phosphorylation, without tau aggregation, because the VQIVYK peptide, that favors aggregation, is missing. On the other hand, when the whole tau protein interacts with thioflavin-S or the peptide VQIVYK, an increase in both aggregation and phosphorylation occurs.

  16. Development of Posiphen, an Inhibitor of Phosphorylated Tau Expression, as a Treatment of TBI

    DTIC Science & Technology

    2015-09-01

    Posiphen reversed this deficit, indicating a beneficial effect of the drug in brain even at the lowest concentration used in this study. We...APP, tau, alpha-synuclein, drug trial 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...clinical studies testing efficacy of this small molecule drug to treat TBI patients. The studies funded to date (“base”) intended to demonstrate

  17. Higgs mediated lepton flavor violating tau decays {tau}{yields}{mu}{gamma} and {tau}{yields}{mu}{gamma}{gamma} in effective theories

    SciTech Connect

    Aranda, J. I.; Tututi, E. S.; Toscano, J. J.

    2008-07-01

    The size of the branching ratios for the {tau}{yields}{mu}{gamma} and {tau}{yields}{mu}{gamma}{gamma} decays induced by a lepton flavor violating Higgs interaction H{tau}{mu} is studied in the framework of effective field theories. The best constraint on the H{tau}{mu} vertex, derived from the know measurement on the muon anomalous magnetic moment, is used to impose the upper bounds Br({tau}{yields}{mu}{gamma})<7.5x10{sup -10} and Br({tau}{yields}{mu}{gamma}{gamma})<2.3x10{sup -12}, which are more stringent than current experimental limits on this class of transitions.

  18. Searches for Lepton Flavor Violation in the Decays tau+- ---> e+- gamma and tau+- ---> mu+- gamma

    SciTech Connect

    Aubert, Bernard; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Battaglia, M.; Brown, David Nathan; Hooberman, B.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; /more authors..

    2010-06-11

    Searches for lepton-flavor-violating decays of a {tau} lepton to a lighter mass lepton and a photon have been performed with the entire dataset of (963 {+-} 7) x 10{sup 6} {tau} decays collected by the BABAR detector near the {Upsilon}(4S), {Upsilon}(3S) and {Upsilon}(2S) resonances. The searches yield no evidence of signals and they set upper limits on the branching fractions of {Beta}({tau}{sup {+-}} {yields} e{sup {+-}}{gamma}) < 3.3 x 10{sup -8} and {Beta}({tau}{sup {+-}} {yields} {mu}{sup {+-}}{gamma}) < 4.4 x 10{sup -8} at 90% confidence level.

  19. Anti-tau antibody reduces insoluble tau and decreases brain atrophy

    PubMed Central

    Yanamandra, Kiran; Jiang, Hong; Mahan, Thomas E; Maloney, Susan E; Wozniak, David F; Diamond, Marc I; Holtzman, David M

    2015-01-01

    Objective We previously found a strong reduction in tau pathology and insoluble tau in P301S tau transgenic mice following intracerebroventricular infusion of the anti-tau antibody HJ8.5. We sought to determine the effects of HJ8.5 in the same model following peripheral administration. Methods The primary objective was to determine if HJ8.5 administered at a dose of 50 mg kg−1 week−1 by intraperitoneal (IP) injection to 6-month-old P301S mice for 3 months would influence phospho-tau (p-tau) accumulation, tau insolubility, and neurodegeneration. Results Treatment with HJ8.5 at 50 mg/kg showed a very strong decrease in detergent-insoluble tau. Importantly, HJ8.5 significantly reduced the loss of cortical and hippocampal tissue volumes compared to control treated mice. HJ8.5 treatment reduced hippocampal CA1 cellular layer staining with the p-tau antibody AT8 and thio-S-positive tau aggregates in piriform cortex and amygdala. Moreover, mice treated with HJ8.5 at 50 mg/kg showed a decrease in motor/sensorimotor deficits compared to vehicle-treated mice. Some effects of HJ8.5, including reduction in brain atrophy, and p-tau immunostaining were also seen with a dose of 10 mg kg−1 week−1. In BV2-microglial cells, we observed significantly higher uptake of P301S tau aggregates in the presence of HJ8.5. HJ8.5 treatment also resulted in a large dose-dependent increase of tau in the plasma. Interpretation Our results indicate that systemically administered anti-tau antibody HJ8.5 significantly decreases insoluble tau, decreases brain atrophy, and improves motor/sensorimotor function in a mouse model of tauopathy. These data further support the idea that anti-tau antibodies should be further assessed as a potential treatment for tauopathies. PMID:25815354

  20. Search for the rare decay B0-->tau+tau- at BABAR.

    PubMed

    Aubert, B; Barate, R; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Pappagallo, M; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Fritsch, M; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Chevalier, N; Cottingham, W N; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Teodorescu, L; Blinov, A E; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Weinstein, A J R; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; del Re, D; Hadavand, H K; Hill, E J; MacFarlane, D B; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Andreassen, R; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nauenberg, U; Olivas, A; Rankin, P; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Harton, J L; Soffer, A; Toki, W H; Wilson, R J; Zeng, Q; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Giraud, P-F; Graziani, G; Hamel de Monchenault, G; Kozanecki, W; Legendre, M; London, G W; Mayer, B; Vasseur, G; Yeche, Ch; Zito, M; Altenburg, D; Feltresi, E; Hauke, A; Spaan, B; Brandt, T; Brose, J; Dickopp, M; Klose, V; Lacker, H M; Nogowski, R; Otto, S; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Bernard, D; Bonneaud, G R; Grenier, P; Schrenk, S; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Xie, Y; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Patteri, P; Peruzzi, I M; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Won, E; Wu, J; Dubitzky, R S; Langenegger, U; Marks, J; Schenk, S; Uwer, U; Martinez-Vidal, F; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Gaillard, J R; Morton, G W; Nash, J A; Nikolich, M B; Taylor, G P; Vazquez, W P; Charles, M J; Mader, W F; Mallik, U; Mohapatra, A K; Cochran, J; Crawley, H B; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Yi, J; Biasini, M; Covarelli, R; Pacetti, S; Pioppi, M; Arnaud, N; Davier, M; Giroux, X; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Oyanguren, A; Petersen, T C; Pierini, M; Plaszczynski, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wormser, G; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Chavez, C A; Forster, Ian J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Parry, R J; Payne, D J; Schofield, K C; Touramanis, C; Cormack, C M; Di Lodovico, F; Menges, W; Sacco, R; Brown, C L; Cowan, G; Flaecher, H U; Green, M G; Hopkins, D A; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Edgar, C L; Hodgkinson, M C; Kelly, M P; Lafferty, G D; Naisbit, M T; Williams, J C; Chen, C; Hulsbergen, W D; Jawahery, A; Kovalskyi, D; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Kofler, R; Koptchev, V B; Li, X; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; Patel, P M; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Cote, D; Taras, P; Viaud, B; Nicholson, H; Baak, M; Bulten, H; Raven, G; Snoek, H L; Wilden, L; Cavallo, N; De Nardo, G; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Jessop, C P; LoSecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Lu, M; Potter, C T; Sinev, N B; Strom, D; Strube, J; Torrence, E; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; de la Vaissiere, C; Del Buono, L; Hamon, O; John, M J J; Leruste, Ph; Malcles, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Cenci, R; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Morganit, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Walsh, J; Haire, M; Judd, D; Wagoner, D E; Biesiada, J; Danielson, N; Elmer, P; Lau, Y; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Safai Tehrani, F; Voena, C; Schröder, H; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Gopal, G P; Olaiya, E O; Wilson, F F; Purohit, M V; Weidemann, A W; Wilson, J R; Yumiceva, F X; Abe, T; Allen, M T; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Claus, R; Coleman, J P; Convery, M R; Cristinziani, M; Dingfelder, J C; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Fan, S; Field, R C; Glanzman, T; Gowdy, S J; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Ahmed, M; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Satpathy, A; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Vitale, L; Panvini, R S; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Kowalewski, R; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Graham, M; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mellado, B; Mihalyi, A; Pan, Y; Prepost, R; Tan, P; von Wimmersperg-Toeller, J H; Wu, S L; Yu, Z; Neal, H; Schott, G

    2006-06-23

    We present the results of a search for the decay B0-->tau+tau- in a data sample of (232+/-3)x10(6) Upsilon(4S)-->BB decays using the BABAR detector. Certain extensions of the standard model predict measurable levels of this otherwise rare decay. We reconstruct fully one neutral B meson and seek evidence for the signal decay in the rest of the event. We find no evidence for signal events and obtain Beta(B0->tau+tau-)<4.1x10(-3) at the 90% confidence level.

  1. Orbital motions and light curves of young binaries XZ Tau and VY Tau

    NASA Astrophysics Data System (ADS)

    Dodin, A. V.; Emelyanov, N. V.; Zharova, A. V.; Lamzin, S. A.; Malogolovets, E. V.; Roe, J. M.

    2016-01-01

    The results of our speckle interferometric observations of young binaries VY Tau and XZ Tau are presented. For the first time, we found a relative displacement of VY Tau components as well as a preliminary orbit for XZ Tau. It appeared that the orbit is appreciably non-circular and is inclined by i ≲ 47◦ from the plane of the sky. It means that the rotation axis of XZ Tau A and the axis of its jet are significantly non-perpendicular to the orbital plane. We found that the average brightness of XZ Tau had been increasing from the beginning of the last century up to the mid-thirties and then it decreased by Δ B > 2 mag. The maximal brightness has been reached significantly later on the time of periastron passage. The total brightness of XZ Tau's components varied in a non-regular way from 1970 to 1985 when eruptions of hot gas from XZ Tau A presumably had occurred. In the early nineties the variations became regular following which a chaotic variability had renewed. We also report that a flare activity of VY Tau has resumed after 40 yr pause, parameters of the previous and new flares are similar, and the flares are related with the A component.

  2. Survey of Volatiles in the Disks Around GV Tau N and AA Tau

    NASA Astrophysics Data System (ADS)

    Gibb, Erika

    2010-02-01

    We propose to use NIRSPEC to characterize the gas phase volatiles, particularly organic molecules, in circumstellar disks toward Tauri stars GV Tau N and AA Tau. These sources have recently been found to exhibit rich molecular absorption (GV Tau N; Gibb et al. 2007) and emission (AA Tau; Carr et al. 2008) spectra that sample distinct regions of the circumstellar disk. If we are to understand the distribution of materials in disks and place our solar system in context, these systems must be studied in detail. As such, we propose to perform a near-infrared survey of these two sources.

  3. Ironing out Tau's Role in Parkinsonism

    PubMed Central

    Stankowski, Jeannette N.; Dawson, Valina L.; Dawson, Ted M.

    2015-01-01

    Parkinson's disease affects more than five million people worldwide, yet no therapeutic has been identified that can slow or halt the progression of this debilitating disease. A new study in tau knockout mice suggests that tau deficiency causes impaired ferroportin-coupled iron export, by retention of the amyloid precursor protein, a neuronal ferroxidase partner, in the endoplasmic reticulum. This leads to parkinsonism through intracellular iron accumulation and degeneration of dopamine neurons (pages X-Y). PMID:22310680

  4. Deletion of endogenous Tau proteins is not detrimental in Drosophila

    PubMed Central

    Burnouf, Sylvie; Grönke, Sebastian; Augustin, Hrvoje; Dols, Jacqueline; Gorsky, Marianna Karina; Werner, Jennifer; Kerr, Fiona; Alic, Nazif; Martinez, Pedro; Partridge, Linda

    2016-01-01

    Human Tau (hTau) is a highly soluble and natively unfolded protein that binds to microtubules within neurons. Its dysfunction and aggregation into insoluble paired helical filaments is involved in the pathogenesis of Alzheimer’s disease (AD), constituting, together with accumulated β-amyloid (Aβ) peptides, a hallmark of the disease. Deciphering both the loss-of-function and toxic gain-of-function of hTau proteins is crucial to further understand the mechanisms leading to neurodegeneration in AD. As the fruit fly Drosophila melanogaster expresses Tau proteins (dTau) that are homologous to hTau, we aimed to better comprehend dTau functions by generating a specific tau knock-out (KO) fly line using homologous recombination. We observed that the specific removal of endogenous dTau proteins did not lead to overt, macroscopic phenotypes in flies. Indeed, survival, climbing ability and neuronal function were unchanged in tau KO flies. In addition, we did not find any overt positive or negative effect of dTau removal on human Aβ-induced toxicity. Altogether, our results indicate that the absence of dTau proteins has no major functional impact on flies, and suggests that our tau KO strain is a relevant model to further investigate the role of dTau proteins in vivo, thereby giving additional insights into hTau functions. PMID:26976084

  5. Targeted deletion of Atg5 reveals differential roles of autophagy in keratin K5-expressing epithelia

    SciTech Connect

    Sukseree, Supawadee; Rossiter, Heidemarie; Mildner, Michael; Pammer, Johannes; Buchberger, Maria; Gruber, Florian; Watanapokasin, Ramida; Tschachler, Erwin; Eckhart, Leopold

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We generated mice lacking Atg5 and autophagy in keratin K5-positive epithelia. Black-Right-Pointing-Pointer Suppression of autophagy in thymic epithelium was not associated with signs of autoimmunity. Black-Right-Pointing-Pointer Autophagy was required for normal terminal differentiation of preputial gland cells. Black-Right-Pointing-Pointer Autophagy-deficient cells of the preputial glands degraded nuclear DNA prematurely. -- Abstract: Autophagy contributes to the homeostasis of many tissues, yet its role in epithelia is incompletely understood. A recent report proposed that Atg5-dependent autophagy in thymic epithelial cells is essential for their function in the negative selection of self-reactive T-cells and, thus, for the suppression of tissue inflammation. Here we crossed mice carrying floxed alleles of the Atg5 gene with mice expressing the Cre recombinase under the control of the keratin K5 promoter to suppress autophagy in all K5-positive epithelia. The efficiency of autophagy abrogation was confirmed by immunoanalyses of LC3, which was converted to the autophagy-associated LC3-II form in normal but not Atg5-deficient cells, and of p62, which accumulated in Atg5-deficient cells. Mice carrying the epithelium-specific deletion of Atg5 showed normal weight gain, absence of tissue inflammation, and a normal morphology of the thymic epithelium. By contrast, autophagy-deficient epithelial cells of the preputial gland showed aberrant eosinophilic staining in histology and premature degradation of nuclear DNA during terminal differentiation. Taken together, the results of this study suggest that autophagy is dispensable for the suppression of autoimmunity by thymic epithelial cells but essential for normal differentiation of the preputial gland in mice.

  6. The winds from HL Tau

    PubMed Central

    Klaassen, P. D.; Mottram, J. C.; Maud, L. T.; Juhasz, A.

    2016-01-01

    Outflowing motions, whether a wind launched from the disc, a jet launched from the protostar, or the entrained molecular outflow, appear to be a ubiquitous feature of star formation. These outwards motions have a number of root causes, and how they manifest is intricately linked to their environment as well as the process of star formation itself. Using the Atacama Large Millimeter/submillimeter Array (ALMA) Science Verification data of HL Tau, we investigate the high-velocity molecular gas being removed from the system as a result of the star formation process. We aim to place these motions in context with the optically detected jet, and the disc. With these high-resolution (∼1 arcsec) ALMA observations of CO (J=1−0), we quantify the outwards motions of the molecular gas. We find evidence for a bipolar outwards flow, with an opening angle, as measured in the redshifted lobe, starting off at 90°, and narrowing to 60° further from the disc, likely because of magnetic collimation. Its outwards velocity, corrected for inclination angle is of the order of 2.4 km s−1. PMID:27559304

  7. Spectroscopy of V471 Tau. I. Review of basic properties

    SciTech Connect

    Bois, B.; Mochnacki, S.W.; Lanning, H.H.

    1988-07-01

    Spectroscopic observations of the eclipsing binary V471 Tau are reported and analyzed. Data obtained mainly in the red band at Mt. Wilson Observatory and KPNO during the period 1975-1983 are compiled in extensive tables and graphs, and the radial velocity of the K dwarf component is determined using a Griffin-mask technique. Results discussed include: (1) distance 44 + or - 6 pc, (consistent with membership in the Hyades), (2) apparent period variation consistent with a third component, (3) emissionlike features affecting the radial-velocity determination, (4) transient features consistent with the presence of flares, and (5) phase-coherent variation in H-alpha (attributed to the action of the white-dwarf Lyman continuum emission on the K dwarf). 70 references.

  8. Vitamin K(3) and K(5) are inhibitors of tumor pyruvate kinase M2.

    PubMed

    Chen, Jing; Jiang, Zheng; Wang, Beibei; Wang, Yanguang; Hu, Xun

    2012-03-28

    Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme of aerobic glycolysis in cancer cells and plays important roles in cancer metabolism and growth. Here we show that vitamin K(3) and K(5) (VK(3) and VK(5)) are relatively specific PKM2 inhibitors. VK(3) and VK(5) showed a significantly stronger potency to inhibit PKM2 than to inhibit PKM1 and PKL, 2 other isoforms of PK dominantly expressed in most adult tissues and liver. This study combined with previous reports supports that VK(3) and VK(5) have potential as adjuvant for cancer chemotherapy.

  9. Naturally Occurring Autoantibodies against Tau Protein Are Reduced in Parkinson's Disease Dementia

    PubMed Central

    Kronimus, Yannick; Albus, Alexandra; Balzer-Geldsetzer, Monika; Straub, Sarah; Semler, Elisa; Otto, Markus; Klotsche, Jens; Dodel, Richard; Mengel, David

    2016-01-01

    Background and Objective Altered levels of naturally occurring autoantibodies (nAbs) against disease-associated neuronal proteins have been reported for neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Recent histopathologic studies suggest a contribution of both Lewy body- and AD-related pathology to Parkinson's disease dementia (PDD). Therefore, we explored nAbs against alpha-synuclein (αS), tau and β-amyloid (Aβ) in PDD compared to cognitively normal PD patients. Materials and Methods We established three different ELISAs to quantify the nAbs-tau, nAbs-αS, and nAbs-Aβ levels and avidity towards their specific antigen in serum samples of 18 non-demented (PDND) and 18 demented PD patients (PDD), which were taken from an ongoing multi-center cohort study (DEMPARK/LANDSCAPE). Results PDD patients had significantly decreased nAbs-tau serum levels compared to PDND patients (p = 0.007), whereas the serum titers of nAbs-αS and nAbs-Aβ were unchanged. For all three nAbs, no significant differences in avidity were found between PDD and PDND cohorts. However, within both patient groups, nAbs-tau showed lowest avidity to their antigen, followed by nAbs-αS, and nAbs-Aβ. Though, due to a high interassay coefficient of variability and the exclusion of many samples below the limit of detection, conclusions for nAbs-Aβ are only conditionally possible. Conclusion We detected a significantly decreased nAbs-tau serum level in PDD patients, indicating a potential linkage between nAbs-tau serum titer and cognitive deficits in PD. Thus, further investigation in larger samples is justified to confirm our findings. PMID:27802290

  10. Electrochemical detection of anti-tau antibodies binding to tau protein and inhibition of GSK-3β-catalyzed phosphorylation.

    PubMed

    Esteves-Villanueva, Jose O; Martic-Milne, Sanela

    2016-03-01

    Tau protein hyperphosphorylation triggers tau aggregation and its toxicity, leading to neuronal death and cell-to-cell toxicity. Hence, inhibition of protein kinases is a viable tool toward reduction of tau toxicity. By targeting various epitopes of Tau441 protein immobilized on Au surface, the protein kinase inhibition by anti-tau antibodies was measured by surface electrochemistry. The electrochemical impedance spectroscopy was used to measure the charge transfer resistance (Rct) of nonphosphorylated tau-Au film (nTau-Au) and compared with the phosphorylated tau-Au film (pTau-Au). The pTau-Au films were characterized by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS), which indicated high phosphorus content. The Rct factor was used as the measure of inhibition efficacies by anti-tau antibodies (D8, A10, P262, and Tau46) in addition to antibody formulation intravenous immunoglobulin (IVIG). The Rct factor for pTau-Au in the absence of antibodies was 0.25 ± 0.08, indicating a dramatic decrease in Rct on phosphorylation. The Rct factors for Tau46 and A10 were 0.57 ± 0.22 and 0.65 ± 0.26, respectively, indicating phosphorylation inhibition. All antibodies exhibited similar binding to nTau-Au. The proposed electrochemical assay may be used for detection of other posttranslational modifications.

  11. The decay. tau. sup minus r arrow K sup minus K sup +. pi. sup minus. nu. sub. tau. and the. nu. sub. tau. mass

    SciTech Connect

    Gomez-Cadenas, J.J. ); Gonzalez-Garcia, M.C.; Pich, A. Instituto de Fisica Corpuscular, Consejo Superior de Investigaciones Cientificas, Universidad de Valencia, Burjasot )

    1990-11-01

    In this paper, we present a model based on the effective chiral Lagrangian to describe the decay {tau}{sup {minus}}{r arrow}{ital K}{sup {minus}}{ital K}{sup +}{pi}{sup {minus}}{nu}{sub {tau}}. Using our model we study the possible limits on the {nu}{sub {tau}} mass that can be achieved by a high-statistics, high-precision experiment taking data close to the {tau}-pair production threshold.

  12. Is the Sky Really Falling?: An Update on the Status of Social Studies in the K-5 Curriculum in Indiana

    ERIC Educational Resources Information Center

    VanFossen, Phillip J.; McGrew, Chris

    2008-01-01

    This study replicates a 2005 study of the status of social studies in the K-5 curriculum in Indiana. The current study reports the results of a comprehensive survey (33 fixed and 2 open-ended) of a stratified (by grade) random sample of K-5 teachers in Indiana (n = 385; response rate = 32%). Results indicated a continued marginalization of social…

  13. Exemplary Literacy Teachers: Promoting Success for All Children in Grades K-5. Solving Problems in the Teaching of Literacy.

    ERIC Educational Resources Information Center

    Block, Cathy Collins; Mangieri, John N.

    This book presents instructional techniques and behaviors that result in the most significant achievement gains for preK-5 students, guiding teachers in assessing their strengths and building their skills within six key domains of literacy instruction directly linked to student success. The book is based on a macroanalysis of preK-5 reading…

  14. Study of the Tau- to Pi- Pi+ Pi- Pi0 Nu/Tau And Tau- to Pi- Pi- Pi+ Eta Nu/Tau Decays Using the BaBar Detector

    SciTech Connect

    Sobie, Randall; /Victoria U.

    2007-11-14

    The {tau}{sup -} {yields} {pi}{sup -}{pi}{sup +}{pi}{sup -}{nu}{sub {tau}} and {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}{eta}{nu}{sub {tau}} decays have been studied with the BABAR detector. Preliminary branching fractions on the two modes are presented. The {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}{eta}{nu}{sub {tau}} mode is found to have a large contribution from the {tau}{sup -} {yields} {omega}{pi}{sup -}{nu}{sub {tau}} decay. The {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}{eta}{nu}{sub {tau}} decay is studied using the {eta} {yields} {gamma}{gamma} mode and the {tau}{sup -} f{sub 1}(1285){pi}{sup -}{nu}{sub {tau}} decay is seen to be the primary source of these decays. A 90% confidence level upper limit is placed on the {tau}{sup -} {yields} {eta}{prime}(958){pi}{sup -}{nu}{sub {tau}} decay which proceeds through a second-class current and is expected to be forbidden in the limit of perfect isospin symmetry.

  15. Horizontal Tau air showers from mountains in deep vally :Traces of Ultrahigh neutrino tau

    NASA Astrophysics Data System (ADS)

    Fargion, Daniele

    1999-08-01

    Ultra High Energy (UHE) Tau neutrino may lead to a very peculiar imprint in future underground K m3 detectors in water and ice as well as in air: rarest secondary tau tracks and decay which may exceed the muon ones. Indeed Bremsstrahlung at high energy lead to longer tracks for heavier leptons. Radiation lenght grows nearly with the square of the lepton mass. Indeed electrons are too light and their trace in matter is negligible (decimeters) muon are much better observed, while tau are too short life time and short range to be found. However, because relativistic time expansion, UHE tau traces in matter, above 1017 eV , are relativistically boosted overcoming the corresponding muon tracks, already bounded by bremsstrahlung logaritmic regime. The tau crossing for Kms in water or ice may be confused with common muon tracks; their tau decay may be missunderstood as muonic catastrophic brehmstrallung interactions. To economize UHE tau dicovery, we suggest to look the tau decay in air into the deep valleys montains, like Canyons or deep in escavation mines where horizontal air showers induce fluoresce or Cerenkov lights. The mountain valley width screens from horizontal secondary muons. The valley height increases the solid angle view. The horizontal air Kms-size gap offer a strong discriminator to filter UHE muons against tau. Tens event a year at PeV ( W resonance peak) energies in K m3 excavation gap should be observable . Hunting air shower in the night toward high mountains in Canyons or in a deep excavation may be the best and cheapest way to discover UHE neutrinos , either born by electron antineutrino scattering on electrons at PeV energies, or by direct tau neutrino possibly relic of muonic flavour oscillation even at EeV energies.

  16. Tau neutrino component to tritium beta decay

    SciTech Connect

    Snyderman, N.J.

    1995-06-01

    A framework is given for explaining anomalous results of neutrino mass experiments that measure the high energy electron spectrum of tritium {beta} decay. The experimental results have been fit to a negative neutrino mass square. We show that there is a consistent phenomenological interpretation due to a positive mass tau neutrino component of the {beta} decay spectrum, with strong near threshold final state interactions with the He nucleus. If this enhancement is due to new interactions between low energy tau neutrinos and nuclei, then the tritium 0 decay experiments could be used as detectors for cosmic background tau neutrinos. The model predicts a distinctive spectrum shape that is consistent with a recent high statistics LLNL experiment. A fit to the experiment gives a tau neutrino mass of 23 eV. Tau neutrinos of this mass would dominate the mass of the universe. Requirements for a theoretical model are given, as well as models that realize different aspects of these requirements. While qualitatively successful, the theoretical models have such severe quantitative difficulties that the accuracy of the molecular physics of the T-{sup 3}He ion, assumed in the analysis of the experimental data, is called into question.

  17. Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology

    PubMed Central

    Maphis, Nicole M.; Jiang, Shanya; Binder, Jessica; Wright, Carrie; Gopalan, Banu; Lamb, Bruce T.; Bhaskar, Kiran

    2017-01-01

    Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer’s disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human MAPT gene under the control of endogenous human MAPT promoter and also were complete knockout for endogenous mouse tau [referred to as ‘hTauMaptKO(Duke)′ mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTauMaptKO(Duke) mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (Prkca), MECP2 (Mecp2), STRN4 (Strn4), SLC40a1 (Slc40a1), POLD2 (Pold2), PCSK2 (Pcsk2), and down-regulated genes: KRT12 (Krt12), LASS1 (Cers1), PLAT (Plat), and NRXN1 (Nrxn1). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTauMaptKO(Duke) mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTauMaptKO(Duke) mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a

  18. Optical variability in the unusual K5 V infrared-excess star HD 98800

    NASA Technical Reports Server (NTRS)

    Henry, Gregory W.; Hall, Douglas S.

    1994-01-01

    The dusty infrared-excess star HD 98800 (K5 V) was observed for several weeks in the spring of 1993 by the Vanderbilt/Tennessee State 0.4 m automatic photoelectric telescope. It was found to be a variable star with an amplitude of 0.07 mag in V and a period of 14.7 days. We show, by comparison with other chromospherically active variable stars and constant stars with good observational histories, that the Rossby number for HD 98800, determined to be 0.30, places it well within the regime of stars whose convective envelopes and rotation rates combine to drive a magnetic dynamo strong enough to generate photometrically observable starspots. The light curve suggests at least two large spots at somewhat different longitudes on HD 98800, one of which could be as large as 16 deg in radius.

  19. Study of the tau- ---> pi- pi- pi+ pi0 pi0 nu/tau and tau- --> 3h- 2h+ nu/tau Decays Using the BaBar Detector

    SciTech Connect

    Sobie, R.; /Victoria U.

    2005-06-21

    The {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}{pi}{sup 0}{pi}{sup 0}{nu}{sub {tau}} and {tau}{sup -} {yields} 3h{sup -} 2h{sup +} {nu}{sub {tau}} decays have been studied using the BABAR experiment at the PEP-II e{sup +}e{sup -} storage ring. Preliminary branching fractions are given for the {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}{pi}{sup 0}{pi}{sup 0}{nu}{sub {tau}} and to the sub-channels {tau}{sup -} {yields} {eta}{pi}{sup -} {pi}{sup 0}{nu}{sub {tau}} and {tau}{sup -} {yields} {omega}(782){pi}{sup -}{pi}{sup 0}{nu}{sub {tau}}. A preliminary upper limit is given on the branching fraction for the {phi}(1020){pi}{sup -}{pi}{sup 0}{nu}{sub {tau}} mode. In addition a preliminary measurement of the branching fraction of the {tau}{sup -} {yields} 3h{sup -}2h{sup +} {nu}{sub {tau}} decay (h = {pi}, K) is presented.

  20. PICALM modulates autophagy activity and tau accumulation

    PubMed Central

    Moreau, Kevin; Fleming, Angeleen; Imarisio, Sara; Lopez Ramirez, Ana; Mercer, Jacob L.; Jimenez-Sanchez, Maria; Bento, Carla F.; Puri, Claudia; Zavodszky, Eszter; Siddiqi, Farah; Lavau, Catherine P.; Betton, Maureen; O’Kane, Cahir J.; Wechsler, Daniel S.; Rubinsztein, David C.

    2014-01-01

    Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover. PMID:25241929

  1. Riluzole Rescues Glutamate Alterations, Cognitive Deficits, and Tau Pathology Associated with P301L Tau Expression

    PubMed Central

    Hunsberger, Holly C.; Weitzner, Daniel S; Rudy, Carolyn C.; Hickman, James E.; Libell, Eric M.; Speer, Rebecca R.; Gerhardt, Greg A.; Reed, Miranda N.

    2016-01-01

    In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. PMID:26146790

  2. The Tau Lepton and the Search for New Elementary Particle Physics

    SciTech Connect

    Perl, Martin L.

    1998-11-18

    This Fifth International WEIN Symposium is devoted to physics beyond the standard model. This talk is about tau lepton physics, but I begin with the question: do we know how to find new physics in the world of elementary particles? This question is interwoven with the various tau physics topics. These topics are: searching for unexpected tau decay modes; searching for additional tau decay mechanisms; radiative tau decays; tau decay modes of the W, B, and D; decay of the Z{sup 0} to tau pairs; searching for CP violation in tau decay; the tau neutrino, dreams and odd ideas in tau physics; and tau research facilities in the next decades.

  3. CP violation in semileptonic tau lepton decays

    SciTech Connect

    Delepine, D.; Castro, G. Lopez; Lozano, L.-T. Lopez

    2005-08-01

    The leading order contribution to the direct CP asymmetry in {tau}{sup {+-}}{yields}K{sup {+-}}{pi}{sup 0}{nu}{sub {tau}} decay rates is evaluated within the standard model. The weak phase required for CP violation is introduced through an interesting mechanism involving second order weak interactions, which is also responsible for tiny violations of the {delta}S={delta}Q rule in K{sub l3} decays. The calculated CP asymmetry turns out to be of order 10{sup -12}, leaving a large window for studying effects of nonstandard sources of CP violation in this observable.

  4. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation.

    PubMed

    Calafate, Sara; Buist, Arjan; Miskiewicz, Katarzyna; Vijayan, Vinoy; Daneels, Guy; de Strooper, Bart; de Wit, Joris; Verstreken, Patrik; Moechars, Diederik

    2015-05-26

    Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer's disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

  5. Multiple-neutral-meson decays of the /tau/ lepton and electromagnetic calorimeter requirements at Tau-Charm Factory

    SciTech Connect

    Gan, K.K.

    1989-08-01

    This is a study of the physics sensitivity to the multiple-neutral-meson decays of the /tau/ lepton at the Tau-Charm Factory. The sensitivity is compared for a moderate and an ultimate electromagnetic calorimeter. With the high luminosity of the Tau- Charm Factory, a very large sample of the decays /tau//sup /minus// /yields/ /pi//sup /minus//2/pi//sup 0//nu//sub /tau// and /tau//sup /minus// /yields/ /pi//sup /minus//3/pi//sup 0//nu//sub /tau// can be collected with both detectors. However, with the ultimate detector, 2/pi//sup 0/ and 3/pi//sup 0/ can be unambiguously reconstructed with very little background. For the suppressed decay /tau//sup /minus// /yields/ /pi//sup /minus///eta//pi//sup 0//nu//sub /tau//, only the ultimate detector has the sensitivity. The ultimate detector is also sensitive to the more suppressed decay /tau//sup /minus// /yields/ K/sup /minus///eta//nu//sub /tau// and the moderate detector may have the sensitivity if the hadronic background is not significantly larger than that predicted by Lund. In the case of the highly suppressed second-class-current decay /tau//sup /minus// /yields/ /pi//sup /minus///eta//nu//sub /tau//, only the ultimate detector has sensitivity. The sensitivity can be greatly enhanced with a small-angle photon veto. 16 refs., 9 figs., 2 tabs.

  6. Search for Second-Class Currents in tau- -> omega.pi-.nu_tau

    SciTech Connect

    Aubert, B.

    2009-04-22

    We report an analysis of {tau}{sup -} decaying into {omega}{pi}{sup -} {nu}{sub {tau}} with {omega} {yields} {pi}{sup +}{pi}{sup -}{pi}{sup 0} using a data sample containing nearly 320 million {tau} pairs collected with the BABAR detector at the PEP-II B-Factory. We find no evidence for second-class currents and we set an upper limit of 0.69% at 90% confidence level for the fraction of second-class currents in this decay mode.

  7. Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal breast epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the breast.

    PubMed

    Boecker, Werner; Stenman, Göran; Schroeder, Tina; Schumacher, Udo; Loening, Thomas; Stahnke, Lisa; Löhnert, Catharina; Siering, Robert Michael; Kuper, Arthur; Samoilova, Vera; Tiemann, Markus; Korsching, Eberhard; Buchwalow, Igor

    2017-03-16

    We contend that knowledge about the cellular composition of normal breast epithelium is a prerequisite for understanding proliferative breast disease. Against this background, we used multicolor immunofluorescence to study normal breast epithelium and two types of intraepithelial proliferative breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal breast epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal breast epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal breast epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal breast epithelium and proliferative breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the breast.

  8. Tau Phosphorylation by GSK3 in Different Conditions

    PubMed Central

    Avila, Jesús; León-Espinosa, Gonzalo; García, Esther; García-Escudero, Vega; Hernández, Félix; DeFelipe, Javier

    2012-01-01

    Almost a 20% of the residues of tau protein are phosphorylatable amino acids: serine, threonine, and tyrosine. In this paper we comment on the consequences for tau of being a phosphoprotein. We will focus on serine/threonine phosphorylation. It will be discussed that, depending on the modified residue in tau molecule, phosphorylation could be protective, in processes like hibernation, or toxic like in development of those diseases known as tauopathies, which are characterized by an hyperphosphorylation and aggregation of tau. PMID:22675648

  9. Recent Results From BaBar in Tau Physics

    SciTech Connect

    Lewczuk, Mateusz; /Victoria U.

    2009-06-25

    The BaBar collaboration has accumulated over 400 million {tau}-pairs which can be used to study charged leptonic and hadronic weak currents to unprecedented precision. This note presents results on lepton universality, measurements of |V{sub us}|, and searches for {tau} decays which violate lepton flavour conservation, or {tau} decays that proceed through a suppressed second class current.

  10. Coefficient Alpha as an Estimate of Test Reliability under Violation of Two Assumptions.

    ERIC Educational Resources Information Center

    Zimmerman, Donald W.; And Others

    1993-01-01

    Coefficient alpha was examined through computer simulation as an estimate of test reliability under violation of two assumptions. Coefficient alpha underestimated reliability under violation of the assumption of essential tau-equivalence of subtest scores and overestimated it under violation of the assumption of uncorrelated subtest error scores.…

  11. Estimation of Tau and Phosphorylated Tau181 in Serum of Alzheimer’s Disease and Mild Cognitive Impairment Patients

    PubMed Central

    Shekhar, Shashank; Kumar, Rahul; Rai, Nitish; Kumar, Vijay; Singh, Kusum; Upadhyay, Ashish Datt; Tripathi, Manjari; Dwivedi, Sadanand; Dey, Aparajit B.; Dey, Sharmistha

    2016-01-01

    The elevated level of cerebrospinal fluid (CSF) Tau and phosphorylated Tau181 (p-Tau181) proteins are well established hallmarks of Alzheimer’s disease (AD). Elevated level of p-Tau181 can differentiate AD from other neurodegenerative disease. However, the expression level of these proteins in serum of AD patient is not well set up. This study sought to evaluate the level of Tau and p-Tau181 in serum of AD, and mild cognitive impairment (MCI) patients for an alternative approach to establish protein-based markers by convenient way. Blood samples were collected from 39 AD patients, 37 MCI patients and 37 elderly individuals as controls. The levels of Tau and p-Tau181 in the serum of the different groups were measured by label free real time Surface Plasmon Resonance technology by using specific antibodies, and were further confirmed by the conventional western blot method. An appropriate statistical analysis, including Receiver Operating Characteristic (ROC), was performed. The concentrations of serum Tau and p-Tau181 were significantly higher (p<0.00001) in AD (Tau; 47.49±9.00ng/μL, p-Tau181; 0.161±0.04 ng/μL) compared to MCI (Tau; 39.26±7.78 ng/μL, p-Tau181; 0.135±0.02 ng/μL) and were further higher compared to elderly controls (Tau; 34.92±6.58 ng/μL, p-Tau181; 0.122±0.01 ng/ μL). A significant (p<0.0001) downhill correlation was found between Tau as well as p-Tau181 levels with HMSE and MoCA score. This study for the first time reports the concentration of Tau and p-Tau181 in serum of AD and MCI patients. The cutoff values of Tau and p-Tau181 of AD and MCI patients with sensitivity and specificity reveal that serum level of these proteins can be used as a predictive marker for AD and MCI. PMID:27459603

  12. Proline Conformation in a Functional Tau Fragment.

    PubMed

    Ahuja, Puneet; Cantrelle, François-Xavier; Huvent, Isabelle; Hanoulle, Xavier; Lopez, Juan; Smet, Caroline; Wieruszeski, Jean-Michel; Landrieu, Isabelle; Lippens, G

    2016-01-16

    The conformational state of distinct prolines can determine the folding of a protein but equally other biological processes when coupled to a conformation-sensitive secondary reaction. For the neuronal tau protein, the importance of proline conformation is underscored by its interaction with different prolyl cis/trans isomerases. The proline conformation would gain even further importance after phosphorylation of the preceding residue by various proline-directed kinases. A number of molecular diseases including Alzheimer's disease and traumatic brain injury were thereby recently qualified as "cistauosis", as they would imply a cis conformation for the pThr231-Pro232 prolyl bond. We here investigate by NMR spectroscopy the conformation of all prolines in a functional Tau fragment, Tau[208-324]. Although we can detect and identify some minor conformers in the cis form, we show that all prolines are for over 90% in the trans conformation. Phosphorylation by CDK2/CycA3, which notably leads to complete modification of the Thr231 residue, does not change this conclusion. Our data hence disagree with the notion that specific prolyl bonds in tau would adopt preferentially the cis conformation.

  13. Search for a low-mass higgs boson in Upsilon(3S)-->gammaA(0), A(0)-->tau(+)tau(-) at BABAR.

    PubMed

    Aubert, B; Karyotakis, Y; Lees, J P; Poireau, V; Prencipe, E; Prudent, X; Tisserand, V; Tico, J Garra; Grauges, E; Martinelli, M; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Battaglia, M; Brown, D N; Kerth, L T; Kolomensky, Yu G; Lynch, G; Osipenkov, I L; Tackmann, K; Tanabe, T; Hawkes, C M; Soni, N; Watson, A T; Koch, H; Schroeder, T; Asgeirsson, D J; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Randle-Conde, A; Blinov, V E; Bukin, A D; Buzykaev, A R; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Atmacan, H; Gary, J W; Liu, F; Long, O; Vitug, G M; Yasin, Z; Sharma, V; Campagnari, C; Hong, T M; Kovalskyi, D; Mazur, M A; Richman, J D; Beck, T W; Eisner, A M; Heusch, C A; Kroseberg, J; Lockman, W S; Martinez, A J; Schalk, T; Schumm, B A; Seiden, A; Wang, L; Winstrom, L O; Cheng, C H; Doll, D A; Echenard, B; Fang, F; Hitlin, D G; Narsky, I; Ongmongkolkul, P; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Bloom, P C; Ford, W T; Gaz, A; Hirschauer, J F; Nagel, M; Nauenberg, U; Smith, J G; Wagner, S R; Ayad, R; Toki, W H; Wilson, R J; Feltresi, E; Hauke, A; Jasper, H; Karbach, T M; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Kobel, M J; Nogowski, R; Schubert, K R; Schwierz, R; Bernard, D; Latour, E; Verderi, M; Clark, P J; Playfer, S; Watson, J E; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Fioravanti, E; Franchini, P; Luppi, E; Munerato, M; Negrini, M; Petrella, A; Piemontese, L; Santoro, V; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Contri, R; Guido, E; Lo Vetere, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Tosi, S; Chaisanguanthum, K S; Morii, M; Adametz, A; Marks, J; Schenk, S; Uwer, U; Bernlochner, F U; Klose, V; Lacker, H M; Lueck, T; Volk, A; Bard, D J; Dauncey, P D; Tibbetts, M; Behera, P K; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Derkach, D; da Costa, J Firmino; Grosdidier, G; Le Diberder, F; Lepeltier, V; Lutz, A M; Malaescu, B; Pruvot, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Touramanis, C; Bevan, A J; Clarke, C K; Di Lodovico, F; Sacco, R; Sigamani, M; Cowan, G; Paramesvaran, S; Wren, A C; Brown, D N; Davis, C L; Denig, A G; Fritsch, M; Gradl, W; Hafner, A; Alwyn, K E; Bailey, D; Barlow, R J; Jackson, G; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Salvati, E; Cowan, R; Dujmic, D; Fisher, P H; Henderson, S W; Sciolla, G; Spitznagel, M; Yamamoto, R K; Zhao, M; Patel, P M; Robertson, S H; Schram, M; Biassoni, P; Lazzaro, A; Lombardo, V; Palombo, F; Stracka, S; Cremaldi, L; Godang, R; Kroeger, R; Sonnek, P; Summers, D J; Zhao, H W; Simard, M; Taras, P; Nicholson, H; De Nardo, G; Lista, L; Monorchio, D; Onorato, G; Sciacca, C; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Wang, W F; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Castelli, G; Gagliardi, N; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Del Amo Sanchez, P; Ben-Haim, E; Bonneaud, G R; Briand, H; Chauveau, J; Hamon, O; Leruste, Ph; Marchiori, G; Ocariz, J; Perez, A; Prendki, J; Sitt, S; Gladney, L; Biasini, M; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Calderini, G; Carpinelli, M; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Lopes Pegna, D; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Anulli, F; Baracchini, E; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Gioi, L Li; Mazzoni, M A; Morganti, S; Piredda, G; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Franek, B; Olaiya, E O; Wilson, F F; Emery, S; Esteve, L; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Allen, M T; Aston, D; Bartoldus, R; Benitez, J F; Cenci, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Sevilla, M Franco; Gabareen, A M; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Lindquist, B; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; Neal, H; Nelson, S; O'Grady, C P; Ofte, I; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; West, C A; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Young, C C; Ziegler, V; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Bellis, M; Burchat, P R; Edwards, A J; Miyashita, T S; Ahmed, S; Alam, M S; Ernst, J A; Pan, B; Saeed, M A; Zain, S B; Soffer, A; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Wray, B C; Drummond, B W; Izen, J M; Lou, X C; Bianchi, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Choi, H H F; Hamano, K; King, G J; Kowalewski, R; Lewczuk, M J; Nugent, I M; Roney, J M; Sobie, R J; Gershon, T J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Puccio, E M T; Band, H R; Chen, X; Dasu, S; Flood, K T; Pan, Y; Prepost, R; Vuosalo, C O; Wu, S L

    2009-10-30

    We search for a light Higgs boson A0 in the radiative decay Upsilon(3S)-->gammaA(0), A(0)-->tau+tau-, tau+-->e+nu(e)nu(tau), or tau+-->mu+nu(mu)nu(tau). The data sample contains 122x10(6) Upsilon(3S) events recorded with the BABAR detector. We find no evidence for a narrow structure in the studied tau+tau- invariant mass region of 4.03tau+tau-)<10.10 GeV/c2. We exclude at the 90% confidence level (C.L.) a low-mass Higgs boson decaying to tau+tau- with a product branching fraction B(Upsilon(3S)-->gammaA(0))xB(A(0)-->tau+tau-)>(1.5-16)x10(-5) across the m(tau+tau-) range. We also set a 90% C.L. upper limit on the tau+tau- decay of the eta(b) at B(eta(b)-->tau+tau-)<8%.

  14. Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer's Disease.

    PubMed

    Pérez, María José; Vergara-Pulgar, Katiana; Jara, Claudia; Cabezas-Opazo, Fabian; Quintanilla, Rodrigo A

    2017-01-13

    Alzheimer's disease (AD) is characterized by the presence of aggregates of tau protein. Tau truncated by caspase-3 (D421) or tau hyperphosphorylated at Ser396/S404 might play a role in the pathogenesis of AD. Mitochondria are dynamic organelles that modify their size and function through mitochondrial dynamics. Recent studies have shown that alterations of mitochondrial dynamics affect synaptic communication. Therefore, we studied the effects of pathological forms of tau on the regulation of mitochondrial dynamics. We used primary cortical neurons from tau(-/-) knockout mice and immortalized cortical neurons (CN1.4) that were transfected with plasmids containing green fluorescent protein (GFP) or GFP with different tau forms: full-length (GFP-T4), truncated (GFP-T4C3), pseudophosphorylated (GFP-T42EC), or both truncated and pseudophosphorylated modifications of tau (GFP-T4C3-2EC). Cells expressing truncated tau showed fragmented mitochondria compared to cells that expressed full-length tau. These findings were corroborated using primary neurons from tau(-/-) knockout mice that expressed the truncated and both truncated and pseudophosphorylated forms of tau. Interestingly, mitochondrial fragmentation was accompanied by a significant reduction in levels of optic atrophy protein 1 (Opa1) in cells expressing the truncated form of tau. In addition, treatment with low concentrations of amyloid-beta (Aβ) significantly reduced mitochondrial membrane potential, cell viability, and mitochondrial length in cortical cells and primary neurons from tau(-/-) mice that express truncated tau. These results indicate that the presence of tau pathology impairs mitochondrial dynamics by reducing Opa1 levels, an event that could lead to mitochondrial impairment observed in AD.

  15. Escitalopram Ameliorates Forskolin-Induced Tau Hyperphosphorylation in HEK239/tau441 Cells.

    PubMed

    Ren, Qing-Guo; Wang, Yan-Juan; Gong, Wei-Gang; Zhou, Qi-Da; Xu, Lin; Zhang, Zhi-Jun

    2015-06-01

    To investigate the effect of escitalopram (a widely used and highly efficacious antidepressant from the SSRI class) on tau hyperphosphorylation, HEK293/tau441 cells were pretreated with 4 μM of forskolin for 2 h. Then we treated the cells with different doses of escitalopram (0, 5, 10, 20, 40, 80 μM) for 22 h. We measured the phosphorylation level of tau by Western blotting. It was shown that escitalopram could protect tau from hyperphosphorylation induced by pharmacological activation of protein kinase A (PKA) at a dose of 20, 40, and 80 μM in vitro. Interestingly, the same dose of escitalopram could also increase the level of serine-9-phosphorylated GSK-3β (inactive form) and the phosphorylation level of Akt at Ser473 (active form) with no significant change in the level of total GSK-3β and Akt. Unexpectedly, 5-hydroxytryptamine 1A receptor (5-HT1A) agonist 8-OH-DPAT did not decrease forskolin-induced tau hyperphosphorylation. Our results suggest that escitalopram can ameliorate forskolin-induced tau hyperphosphorylation, which is not through the typical 5-HT1A pathway, and Akt/GSK-3β signaling pathway is involved. These findings may support an effective role of antidepressants in the prevention of dementia associated with depression in patients.

  16. Resolved multifrequency radio observations of GG Tau

    SciTech Connect

    Andrews, Sean M.; Birnstiel, T.; Rosenfeld, K. A.; Wilner, D. J.; Chandler, Claire J.; Pérez, L. M.; Isella, Andrea; Ricci, L.; Carpenter, J. M.; Calvet, N.; Corder, S. A.; Deller, A. T.; Dullemond, C. P.; Greaves, J. S.; Harris, R. J.; Henning, Th.; Linz, H.; Kwon, W.; Lazio, J.; Mundy, L. G.; and others

    2014-06-01

    We present subarcsecond resolution observations of continuum emission associated with the GG Tau quadruple star system at wavelengths of 1.3, 2.8, 7.3, and 50 mm. These data confirm that the GG Tau A binary is encircled by a circumbinary ring at a radius of 235 AU with a FWHM width of ∼60 AU. We find no clear evidence for a radial gradient in the spectral shape of the ring, suggesting that the particle size distribution is spatially homogeneous on angular scales ≳0.''1. A central point source, likely associated with the primary component (GG Tau Aa), exhibits a composite spectrum from dust and free-free emission. Faint emission at 7.3 mm is observed toward the low-mass star GG Tau Ba, although its origin remains uncertain. Using these measurements of the resolved, multifrequency emission structure of the GG Tau A system, models of the far-infrared to radio spectrum are developed to place constraints on the grain size distribution and dust mass in the circumbinary ring. The non-negligible curvature present in the ring spectrum implies a maximum particle size of 1-10 mm, although we are unable to place strong constraints on the distribution shape. The corresponding dust mass is 30-300 M {sub ⊕}, at a temperature of 20-30 K. We discuss how this significant concentration of relatively large particles in a narrow ring at a large radius might be produced in a local region of higher gas pressures (i.e., a particle 'trap') located near the inner edge of the circumbinary disk.

  17. Review of recent results on the /tau/ lepton

    SciTech Connect

    Gan, K.K.

    1988-04-01

    This is a review of the recent results on the /tau/ lepton. The results include precise measurements of the lifetime, measurements of the decay /tau//sup /minus// ..-->.. ..pi../sup /minus//2..pi../sup 0/..nu../sub /tau// with much improved precision, limits on decay modes containing /eta/ mesons, including the second-class-current decay /tau//sup /minus// ..-->.. ..pi../sup /minus///eta/..nu../sub /tau//, and limits on exotic decay modes. The implications of these results on the discrepancy in the one-charged-particle decay modes are discussed. 43 refs., 4 figs., 2 tabs.

  18. Discodermolide interferes with the binding of tau protein to microtubules.

    PubMed

    Kar, Santwana; Florence, Gordon J; Paterson, Ian; Amos, Linda A

    2003-03-27

    We investigated whether discodermolide, a novel antimitotic agent, affects the binding to microtubules of tau protein repeat motifs. Like taxol, the new drug reduces the proportion of tau that pellets with microtubules. Despite their differing structures, discodermolide, taxol and tau repeats all bind to a site on beta-tubulin that lies within the microtubule lumen and is crucial in controlling microtubule assembly. Low concentrations of tau still bind strongly to the outer surfaces of preformed microtubules when the acidic C-terminal regions of at least six tubulin dimers are available for interaction with each tau molecule; otherwise binding is very weak.

  19. Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Aβ) peptide and phospho-tau.

    PubMed

    Ray, Balmiki; Reyes, Patricio F; Lahiri, Debomoy K

    2011-04-01

    Normal Pressure Hydrocephalus (NPH) is one of the causes of dementia of the elderly characterized by impaired mental function, gait difficulties and urinary incontinence. Previously, it was proposed that some of the NPH patients may develop Alzheimer's disease (AD) like pathology. Aim of this study was to compare levels of different CSF biomarkers, including total secreted β-amyloid precursor protein (sAPP), sAPP-alpha form (sAPPα), amyloid-beta (Aβ) peptide, total-tau protein and hyperphosphorylated-tau protein in subjects from NPH and Non-NPH Control (NNC). CSF was collected from 23 NPH patients and 13 Non-NPH controls by lumber puncture. Western blot analysis was performed to measure levels of sAPP-total. ELISA was used separately to determine levels of sAPPα, Aβ peptide, total-tau and phospho-tau proteins. We found a significant decrease in levels of total secreted APP, sAPPα and Aβ (1-42) in the CSF sample of NPH patients vs. NNC. We did not observe any change in levels of total-tau or phospho-tau in NPH vs. NNC subjects. Notably, phospho-tau level was significantly increased in the NPH patients, who were suffering from the disease for more than one year, vs. NNC. Among five biomarkers studied, decreased sAPP, sAPPα and Aβ (1-42) levels in CSF can be molecular markers to distinguish NPH cases from NNC. Disease severity can also be assessed by increased levels of CSF phospho-tau protein and the ratio of phospho-tau to Aβ (1-42), which might be a useful tool for predicting conversion of NPH individuals to other neurodegenerative disorders including Alzheimer's disease (AD).

  20. Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice*

    PubMed Central

    Ma, Qiu-Lan; Zuo, Xiaohong; Yang, Fusheng; Ubeda, Oliver J.; Gant, Dana J.; Alaverdyan, Mher; Teng, Edmond; Hu, Shuxin; Chen, Ping-Ping; Maiti, Panchanan; Teter, Bruce; Cole, Greg M.; Frautschy, Sally A.

    2013-01-01

    The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected. PMID:23264626

  1. Tau mis-splicing in the pathogenesis of neurodegenerative disorders

    PubMed Central

    Park, Sun Ah; Ahn, Sang Il; Gallo, Jean-Marc

    2016-01-01

    Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413] PMID:27222125

  2. The disk around the brown dwarf KPNO Tau 3

    SciTech Connect

    Broekhoven-Fiene, Hannah; Matthews, Brenda; Di Francesco, James; Duchêne, Gaspard; Scholz, Aleks; Chrysostomou, Antonio; Jayawardhana, Ray

    2014-07-10

    We present submillimeter observations of the young brown dwarfs KPNO Tau 1, KPNO Tau 3, and KPNO Tau 6 at 450 μm and 850 μm taken with the Submillimetre Common-User Bolometer Array on the James Clerk Maxwell Telescope. KPNO Tau 3 and KPNO Tau 6 have been previously identified as Class II objects hosting accretion disks, whereas KPNO Tau 1 has been identified as a Class III object and shows no evidence of circumsubstellar material. Our 3σ detection of cold dust around KPNO Tau 3 implies a total disk mass of (4.0 ± 1.1) × 10{sup –4} M{sub ☉} (assuming a gas to dust ratio of 100:1). We place tight constraints on any disks around KPNO Tau 1 or KPNO Tau 6 of <2.1 × 10{sup –4} M{sub ☉} and <2.7 × 10{sup –4} M{sub ☉}, respectively. Modeling the spectral energy distribution of KPNO Tau 3 and its disk suggests the disk properties (geometry, dust mass, and grain size distribution) are consistent with observations of other brown dwarf disks and low-mass T-Tauri stars. In particular, the disk-to-host mass ratio for KPNO Tau 3 is congruent with the scenario that at least some brown dwarfs form via the same mechanism as low-mass stars.

  3. Dimer model for Tau proteins bound in microtubule bundles

    NASA Astrophysics Data System (ADS)

    Hall, Natalie; Kluber, Alexander; Hayre, N. Robert; Singh, Rajiv; Cox, Daniel

    2013-03-01

    The microtubule associated protein tau is important in nucleating and maintaining microtubule spacing and structure in neuronal axons. Modification of tau is implicated as a later stage process in Alzheimer's disease, but little is known about the structure of tau in microtubule bundles. We present preliminary work on a proposed model for tau dimers in microtubule bundles (dimers are the minimal units since there is one microtubule binding domain per tau). First, a model of tau monomer was created and its characteristics explored using implicit solvent molecular dynamics simulation. Multiple simulations yield a partially collapsed form with separate positively/negatively charged clumps, but which are a factor of two smaller than required by observed microtubule spacing. We argue that this will elongate in dimer form to lower electrostatic energy at a cost of entropic ``spring'' energy. We will present preliminary results on steered molecular dynamics runs on tau dimers to estimate the actual force constant. Supported by US NSF Grant DMR 1207624.

  4. Survivability of Psychrobacter cryohalolentis K5 Under Simulated Martian Surface Conditions

    NASA Astrophysics Data System (ADS)

    Smith, David J.; Schuerger, Andrew C.; Davidson, Mark M.; Pacala, Stephen W.; Bakermans, Corien; Onstott, Tullis C.

    2009-03-01

    Spacecraft launched to Mars can retain viable terrestrial microorganisms on board that may survive the interplanetary transit. Such biota might compromise the search for life beyond Earth if capable of propagating on Mars. The current study explored the survivability of Psychrobacter cryohalolentis K5, a psychrotolerant microorganism obtained from a Siberian permafrost cryopeg, under simulated martian surface conditions of high ultraviolet irradiation, high desiccation, low temperature, and low atmospheric pressure. First, a desiccation experiment compared the survival of P. cryohalolentis cells embedded, or not embedded, within a medium/salt matrix (MSM) maintained at 25°C for 24 h within a laminar flow hood. Results indicate that the presence of the MSM enhanced survival of the bacterial cells by 1 to 3 orders of magnitude. Second, tests were conducted in a Mars Simulation Chamber to determine the UV tolerance of the microorganism. No viable vegetative cells of P. cryohalolentis were detected after 8 h of exposure to Mars-normal conditions of 4.55 W/m2 UVC irradiation (200-280 nm), -12.5°C, 7.1 mbar, and a Mars gas mix composed of CO2 (95.3%), N2 (2.7%), Ar (1.6%), O2 (0.2%), and H2O (0.03%). Third, an experiment was conducted within the Mars chamber in which total atmospheric opacities were simulated at τ = 0.1 (dust-free CO2 atmosphere at 7.1 mbar), 0.5 (normal clear sky with 0.4 = dust opacity and 0.1 = CO2-only opacity), and 3.5 (global dust storm) to determine the survivability of P. cryohalolentis to partially shielded UVC radiation. The survivability of the bacterium increased with the level of UVC attenuation, though population levels still declined several orders of magnitude compared to UVC-absent controls over an 8 h exposure period.

  5. Observation of CO2 in Comet C/2012 K5 LINEAR

    NASA Astrophysics Data System (ADS)

    McKay, Adam; Kelley, Michael; DiSanti, Michael; Chanover, Nancy

    2012-12-01

    The study of cometary composition is important to understanding the formation and evolution of our solar system. Comets have undergone very little thermal evolution in their lifetimes, which results in their near pristine composition. The nucleus of a comet is very rarely detected directly. Instead, we observe the coma that surrounds the nucleus. Physical and chemical processes in the coma affect its composition, and therefore coma composition is not a direct representation of nuclear composition. An important trend is the observed variation of coma composition with heliocentric distance, most likely influenced by the volatility of the main surface ices, H2O, CO2, and CO. Infrared studies of these molecules are complicated by telluric features, so often daughter molecules of these species such as OH are observed instead. A potentially effective tracer for these primary ices is atomic oxygen in the coma. However, the relationship between these ices and atomic oxygen is only understood at a qualitative level. We propose to use Spitzer observations in IRAC's 4.5 micron band pass to observe the CO2 v3 band at 4.26 microns in comet C/2012 K5 LINEAR. These observations will be coordinated with observations of atomic oxygen obtained at Apache Point Observatory and observations of H2O at Keck. These near simultaneous observations of H2O, CO2, and atomic oxygen in a cometary coma will increase our understanding of the link between these primary ices and atomic oxygen. With a complete understanding of the relationship between atomic oxygen and the primary ices on the nucleus, observations of atomic oxygen can serve as a powerful proxy for the production of these primary volatiles and aid our understanding of the variation in coma composition as a function of heliocentric distance, and therefore the composition of the nucleus and how our solar system was formed.

  6. An unexpected oxidation: NaK5Cl2(S2O6)2 revisited

    PubMed Central

    Harrison, William T. A.; Plater, M. John

    2017-01-01

    The title compound, NaK5Cl2(S2O6)2 [systematic name: sodium penta­potassium dichloride bis­(di­thio­nate)], arose as an unexpected product from an organic synthesis that used di­thio­nite (S2O4 2−) ions as a reducing agent to destroy excess permanganate ions. Compared to the previous study [Stanley (1953 ▸). Acta Cryst. 6, 187–196], the present tetra­gonal structure exhibits a root 2a × root 2a × c super-cell due to subtle changes in the orientations of the di­thio­nate anions. The structure can be visualized as a three-dimensional framework of [001] columns of alternating trans-NaO4Cl2 and KO4Cl2 octa­hedra cross-linked by the di­thio­nate ions with the inter­stices occupied by KO6Cl2 polyhedra to generate a densely packed three-dimensional framework. The asymmetric unit comprises two sodium ions (site symmetries 4 and -4, four potassium ions (site symmetries = -4, 4, 1 and 1), three chloride ions (site symmetries = 4, 4 and 2) and two half-di­thio­nate ions (all atoms on general positions). Both di­thio­nate ions are completed by crystallographic inversion symmetry. The crystal chosen for data collection was found to be rotationally twinned by 180° about the [100] axis in reciprocal space with a 0.6298 (13):0.3702 (13) domain ratio. PMID:28217339

  7. Total-tau and phospho-tau(181Thr) in cerebrospinal fluid of neurologically intact population increase with age.

    PubMed

    Jaworski, J; Psujek, M; Bartosik-Psujek, H

    2009-01-01

    Tau protein is a microtubule-associated molecule playing a crucial role in maintenance of neuronal integrity and in many neurodegenerative processes; its pathology has become a hallmark feature at the tissue level. The aim of the study was to estimate total tau and phospho-tau (Thr181) concentrations in cerebrospinal fluid of healthy population. Cerebrospinal fluid samples were taken from 129 subjects (age 18-77 years) without known neurologic or psychiatric condition. Both total-tau and phospho-tau levels showed significant correlation with age, which was more pronounced in older population.

  8. EFFECT OF DUST ON Ly{alpha} PHOTON TRANSFER IN AN OPTICALLY THICK HALO

    SciTech Connect

    Yang Yang; Shu Chiwang; Roy, Ishani; Fang Lizhi

    2011-10-01

    We investigate the effects of dust on Ly{alpha} photons emergent from an optically thick medium by solving the integro-differential equation of radiative transfer of resonant photons. To solve the differential equations numerically, we use the weighted essentially non-oscillatory method. Although the effects of dust on radiative transfer are well known, the resonant scattering of Ly{alpha} photons makes the problem non-trivial. For instance, if the medium has an optical depth of dust absorption and scattering of {tau}{sub a} >> 1, {tau} >> 1, and {tau} >> {tau}{sub a}, the effective absorption optical depth in a random walk scenario would be equal to {radical}({tau}{sub a}({tau}{sub a}+{tau})). We show, however, that for a resonant scattering at frequency {nu}{sub 0}, the effective absorption optical depth would be even larger than {tau}({nu}{sub 0}). If the cross section of dust scattering and absorption is frequency-independent, the double-peaked structure of the frequency profile given by the resonant scattering is basically dust-independent. That is, dust causes neither narrowing nor widening of the width of the double-peaked profile. One more result is that the timescales of the Ly{alpha} photon transfer in an optically thick halo are also basically independent of the dust scattering, even when the scattering is anisotropic. This is because those timescales are mainly determined by the transfer in the frequency space, while dust scattering, either isotropic or anisotropic, does not affect the behavior of the transfer in the frequency space when the cross section of scattering is wavelength-independent. This result does not support the speculation that dust will lead to the smoothing of the brightness distribution of a Ly{alpha} photon source with an optically thick halo.

  9. Maternal entrainment of tau mutant hamsters.

    PubMed

    Viswanathan, N; Davis, F C

    1992-01-01

    Maternal entrainment of the circadian wheel-running activity rhythm was examined in Syrian hamsters heterozygous for a single gene mutation (tau) that affects the free-running period of circadian rhythms. Heterozygous tau pups were born to and raised by wild-type mothers under constant dim light. The pups' wheel-running activity was recorded after weaning on postnatal day 18 or 24. Pups weaned on day 18 had an average free-running period of 21.70 hr, demonstrating that the tau phenotype was fully expressed at this age. Using the activity onset of the postnatal free-running rhythms as a phase reference, we estimated the phase relationships between the pups and their mothers on days 18 and 24. In contrast to results with wild-type pups, the activity rhythms of tau pups were not in phase with the rhythms of their wild-type mothers; that is, activity onsets of mothers and pups did not coincide. The pups did, however, show synchrony among themselves, indicating that they had been exposed to a synchronizing signal sometime during development. It is likely that this synchronizing signal was provided by the mothers, since pups from different litters showed phase relationships similar to those of their mothers. Thus the mothers provided a signal that was sufficient to cause entrainment, despite the 2-hr difference in free-running period between the mothers and pups. Although the pups' activity rhythms appeared to have been entrained by the mothers, they were clearly free-running by postnatal day 18. The mechanism for entrainment is lost during the course of development, despite continued interaction between the mothers and pups.

  10. The Copernicus ultraviolet spectral atlas Tau Scorpii

    NASA Technical Reports Server (NTRS)

    Rogerson, J. B., Jr.; Upson, W. L., II

    1977-01-01

    An ultraviolet spectral atlas was presented for the B0 V star, Tau Scorpii. It was scanned from 949 to 1560 A by the Princeton spectrometer aboard the Copernicus satellite. From 949 to 1420 A the observations have a nominal resolution of 0.05 A. At the longer wavelengths, the resolution was 0.1 A. The atlas was presented in both tables and graphs.

  11. CSF tau levels influence cortical plasticity in Alzheimer's disease patients.

    PubMed

    Koch, Giacomo; Esposito, Zaira; Kusayanagi, Hajime; Monteleone, Fabrizia; Codecá, Claudia; Di Lorenzo, Francesco; Caltagirone, Carlo; Bernardi, Giorgio; Martorana, Alessandro

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative process characterized by progressive neuronal degeneration, reduced levels of neurotransmitters, and altered forms of synaptic plasticity. In animal models of AD, amyloid-β (Aβ) and tau proteins are supposed to interfere with synaptic transmission. In the current study, we investigated the correlation between motor cortical plasticity, measured with 1 Hz repetitive transcranial magnetic stimulation (rTMS), and the levels of Aβ₁₋₄₂, total tau (t-Tau), and phosphorylated tau (p-Tau) detected in cerebrospinal fluid (CSF) of AD patients. We found that the overall rTMS after effects were milder in AD patients in comparison with controls. In AD patients the amount of rTMS-induced inhibition correlated with CSF t-Tau, but not with Aβ₁₋₄₂ CSF levels. Surprisingly, higher CSF t-Tau levels were associated to a stronger inhibition of the motor evoked potentials, implying that the expected effects of the 1 Hz rTMS protocol were more evident in patients with more pathological t-Tau CSF levels. These data could be interpreted as the consequence of CSF t-Tau mediated abnormal excitatory activity and could suggest that CSF t-Tau may impact mechanisms of cortical plasticity.

  12. Hyperphosphorylation results in tau dysfunction in DNA folding and protection.

    PubMed

    Lu, Yang; He, Hai-Jin; Zhou, Jun; Miao, Jun-Ye; Lu, Jing; He, Ying-Ge; Pan, Rong; Wei, Yan; Liu, Ying; He, Rong-Qiao

    2013-01-01

    Hyperphosphorylation of tau occurs in preclinical and clinical stages of Alzheimer's disease (AD), and hyperphosphorylated tau is the main constituent of the paired helical filaments in the brains of mild cognitive impairment and AD patients. While most of the work described so far focused on the relationship between hyperphosphorylation of tau and microtubule disassembly as well as axonal transport impairments, both phenomena ultimately leading to cell death, little work has been done to study the correlation between tau hyperphosphorylation and DNA damage. As we showed in this study, tau hyperphosphorylation and DNA damage co-occurred under formaldehyde treatment in N2a cells, indicating that phosphorylated tau (p-Tau) induced by formaldehyde may be involved in DNA impairment. After phosphorylation, the effect of tau in preventing DNA from thermal denaturation was diminished, its ability to accelerate DNA renaturation was lost, and its function in protecting DNA from reactive oxygen species (ROS) attack was impaired. Thus, p-Tau is not only associated with the disassembly of the microtubule system, but also plays a crucial role in DNA impairment. Hyperphosphorylation-mediated dysfunction of tau protein in prevention of DNA structure from damage under the attack of ROS may provide novel insights into the mechanisms underlying tauopathies.

  13. Interactions between Aβ and Mutated Tau Lead to Polymorphism and Induce Aggregation of Aβ-Mutated Tau Oligomeric Complexes

    PubMed Central

    Raz, Yoav; Miller, Yifat

    2013-01-01

    One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ∆K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer’s disease Aβ peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between Aβ and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between Aβ and mutated tau, we constructed fourteen ∆K280 mutated tau-Aβ17-42 oligomeric complexes. In seven of the mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-Aβ17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and Aβ oligomers: interactions of one monomer of the Aβ oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire Aβ oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of Aβ trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of Aβ and mutated tau oligomers, polymorphic mutated tau-Aβ17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. Aβ trimers alternating with mutated tau trimers constituted a structurally stable confined β-structure, albeit one that was

  14. Tau flavored dark matter and its impact on tau Yukawa coupling

    NASA Astrophysics Data System (ADS)

    Chao, Wei; Guo, Huai-Ke; Li, Hao-Lin

    2017-02-01

    In this paper we perform a systematic study of the tau flavored dark matter (DM) model by introducing two kinds of mediators (a scalar doublet and a charged scalar singlet). The electromagnetic properties of the DM, as well as their implications in DM direct detections, are analyzed in detail. The model turns out contributing a significant radiative correction to the tau lepton mass, in addition to loosing the tension between the measured DM relic density and constraints of DM direct detections. The loop corrections can be Script O(10%) of the total tau mass. Signal rates of the Higgs measurements from the LHC in the h→τ τ and h→ γ γ channels, relative to the Standard Model expectations, can be explained in this model.

  15. Search for tau- ---> 4pi- 3pi+ (pi0) nu/tau Decays

    SciTech Connect

    Ter-Antonian, R.; Kass, R.; Allmendinger, T.; Hast, C.; /SLAC

    2005-06-21

    A search for the decay of the {tau} lepton to seven charged pions and at most one {pi}{sup 0} was performed using the BABAR detector at the PEP-II e{sup +}e{sup -} collider. The analysis uses data recorded on and near the {Upsilon}(4S) resonance between 1999 and 2003, a total of 124.3 fb{sup -1}. They observe 7 events with an expected background of 11.9 {+-} 2.2 events and calculate a preliminary upper limit of BR({tau}{sup -} {yields} 4{pi}{sup -} 3{pi}{sup +}({pi}{sup 0}){nu}{sub {tau}}) < 2.7 x 10{sup -7} at 90% CL. This is a significant improvement over the previous limit established by the CLEO Collaboration.

  16. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo

    PubMed Central

    Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong; Mahan, Thomas E.; Ma, Shengmei; Maloney, Susan E.; Wozniak, David F.

    2014-01-01

    Summary Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. Trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein, and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused 3 effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy. PMID:24075978

  17. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo.

    PubMed

    Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong; Mahan, Thomas E; Ma, Shengmei; Maloney, Susan E; Wozniak, David F; Diamond, Marc I; Holtzman, David M

    2013-10-16

    Tau aggregation occurs in neurodegenerative diseases including Alzheimer's disease and many other disorders collectively termed tauopathies. trans-cellular propagation of tau pathology, mediated by extracellular tau aggregates, may underlie pathogenesis of these conditions. P301S tau transgenic mice express mutant human tau protein and develop progressive tau pathology. Using a cell-based biosensor assay, we screened anti-tau monoclonal antibodies for their ability to block seeding activity present in P301S brain lysates. We infused three effective antibodies or controls into the lateral ventricle of P301S mice for 3 months. The antibodies markedly reduced hyperphosphorylated, aggregated, and insoluble tau. They also blocked development of tau seeding activity detected in brain lysates using the biosensor assay, reduced microglial activation, and improved cognitive deficits. These data imply a central role for extracellular tau aggregates in the development of pathology. They also suggest that immunotherapy specifically designed to block trans-cellular aggregate propagation will be a productive treatment strategy.

  18. Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss

    PubMed Central

    Tiwari, Sachin Suresh; Mizuno, Keiko; Ghosh, Anshua; Aziz, Wajeeha; Troakes, Claire; Daoud, Jason; Golash, Vidushi; Noble, Wendy; Hortobágyi, Tibor

    2016-01-01

    Characteristic features of Alzheimer’s disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer’s disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ∼50% in severe Alzheimer’s hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer’s disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer’s disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-β42. Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also

  19. Tau protein is essential for stress-induced brain pathology

    PubMed Central

    Lopes, Sofia; Vaz-Silva, João; Pinto, Vitor; Dalla, Christina; Kokras, Nikolaos; Bedenk, Benedikt; Mack, Natalie; Czisch, Michael; Almeida, Osborne F. X.; Sousa, Nuno; Sotiropoulos, Ioannis

    2016-01-01

    Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer’s-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function. PMID:27274066

  20. Search for the rare leptonic decay B--->tau-nutau.

    PubMed

    Aubert, B; Barate, R; Boutigny, D; Couderc, F; Gaillard, J-M; Hicheur, A; Karyotakis, Y; Lees, J P; Tisserand, V; Zghiche, A; Palano, A; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Borgland, A W; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Shelkov, V G; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Fritsch, M; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Steinke, M; Boyd, J T; Chevalier, N; Cottingham, W N; Kelly, M P; Latham, T E; Wilson, F F; Cuhadar-Donszelmann, T; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Thiessen, D; Khan, A; Kyberd, P; Teodorescu, L; Blinov, A E; Blinov, V E; Druzhinin, V P; Golubev, V B; Ivanchenko, V N; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bruinsma, M; Chao, M; Eschrich, I; Kirkby, D; Lankford, A J; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Foulkes, S D; Gary, J W; Shen, B C; Wang, K; Del Re, D; Hadavand, H K; Hill, E J; Macfarlane, D B; Paar, H P; Rahatlou, Sh; Sharma, V; Berryhill, J W; Campagnari, C; Dahmes, B; Levy, S L; Long, O; Lu, A; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Eisner, A M; Heusch, C A; Lockman, W S; Nesom, G; Schalk, T; Schmitz, R E; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Yang, S; Jayatilleke, S; Mancinelli, G; Meadows, B T; Sokoloff, M D; Abe, T; Blanc, F; Bloom, P; Chen, S; Ford, W T; Nauenberg, U; Olivas, A; Rankin, P; Smith, J G; Zhang, J; Zhang, L; Chen, A; Harton, J L; Soffer, A; Toki, W H; Wilson, R J; Zeng, Q L; Altenburg, D; Brandt, T; Brose, J; Dickopp, M; Feltresi, E; Hauke, A; Lacker, H M; Müller-Pfefferkorn, R; Nogowski, R; Otto, S; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Spaan, B; Sundermann, J E; Bernard, D; Bonneaud, G R; Brochard, F; Grenier, P; Schrenk, S; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Bard, D J; Clark, P J; Lavin, D; Muheim, F; Playfer, S; Xie, Y; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Sarti, A; Treadwell, E; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Patteri, P; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Crosetti, G; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Bailey, S; Brandenburg, G; Morii, M; Won, E; Dubitzky, R S; Langenegger, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Gaillard, J R; Morton, G W; Nash, J A; Nikolich, M B; Taylor, G P; Charles, M J; Grenier, G J; Mallik, U; Cochran, J; Crawley, H B; Lamsa, J; Meyer, W T; Prell, S; Rosenberg, E I; Yi, J; Davier, M; Grosdidier, G; Höcker, A; Laplace, S; Le Diberder, F; Lepeltier, V; Lutz, A M; Petersen, T C; Plaszczynski, S; Schune, M H; Tantot, L; Wormser, G; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Chavez, C A; Coleman, J P; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Parry, R J; Payne, D J; Sloane, R J; Touramanis, C; Back, J J; Cormack, C M; Harrison, P F; Di Lodovico, F; Mohanty, G B; Brown, C L; Cowan, G; Flack, R L; Flaecher, H U; Green, M G; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Winter, M A; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Hodgkinson, M C; Lafferty, G D; Lyon, A J; Williams, J C; Farbin, A; Hulsbergen, W D; Jawahery, A; Kovalskyi, D; Lae, C K; Lillard, V; Roberts, D A; Blaylock, G; Dallapiccola, C; Flood, K T; Hertzbach, S S; Kofler, R; Koptchev, V B; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Sciolla, G; Taylor, F; Yamamoto, R K; Mangeol, D J J; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Taras, P; Nicholson, H; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Wilden, L; Jessop, C P; Losecco, J M; Gabriel, T A; Allmendinger, T; Brau, B; Gan, K K; Honscheid, K; Hufnagel, D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Potter, C T; Sinev, N B; Strom, D; Torrence, E; Colecchia, F; Dorigo, A; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Tiozzo, G; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; de la Vaissière, Ch; Del Buono, L; Hamon, O; John, M J J; Leruste, Ph; Malcles, J; Ocariz, J; Pivk, M; Roos, L; T'jampens, S; Therin, G; Manfredi, P F; Re, V; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Anulli, F; Biasini, M; Peruzzi, I M; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bondioli, M; Bucci, F; Calderini, G; Carpinelli, M; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Martinez-Vidal, F; Morganti, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Sandrelli, F; Walsh, J; Haire, M; Judd, D; Paick, K; Wagoner, D E; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Miftakov, V; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Pierini, M; Piredda, G; Tehrani, F Safai; Voena, C; Christ, S; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Geddes, N I; Gopal, G P; Olaiya, E O; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Giraud, P-F; de Monchenault, G Hamel; Kozanecki, W; Langer, M; Legendre, M; London, G W; Mayer, B; Schott, G; Vasseur, G; Yèche, Ch; Zito, M; Purohit, M V; Weidemann, A W; Wilson, J R; Yumiceva, F X; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Claus, R; Convery, M R; Cristinziani, M; De Nardo, G; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Elsen, E E; Fan, S; Field, R C; Glanzman, T; Gowdy, S J; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Petrak, S; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Simi, G; Snyder, A; Soha, A; Stelzer, J; Su, D; Sullivan, M K; Va'vra, J; Wagner, S R; Weaver, M; Weinstein, A J R; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Young, C C; Burchat, P R; Edwards, A J; Meyer, T I; Petersen, B A; Roat, C; Ahmed, S; Alam, M S; Ernst, J A; Saeed, M A; Saleem, M; Wappler, F R; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Kim, H; Ritchie, J L; Satpathy, A; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Borean, C; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Poropat, P; Vitale, L; Vuagnin, G; Panvini, R S; Banerjee, Sw; Brown, C M; Fortin, D; Jackson, P D; Kowalewski, R; Roney, J M; Sobie, R J; Band, H R; Dasu, S; Datta, M; Eichenbaum, A M; Graham, M; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mihalyi, A; Mohapatra, A K; Pan, Y; Prepost, R; Rubin, A E; Sekula, S J; Tan, P; von Wimmersperg-Toeller, J H; Wu, J; Wu, S L; Yu, Z; Greene, M G; Neal, H

    2005-07-22

    We present a search for the decay B(-)--> tau(-)nu(tau) in a sample of 88.9 x 10(6) BB pairs recorded with the BABAR detector at the Stanford Linear Accelerator Center B factory. One of the two B mesons from the Gamma(4S) is reconstructed in a hadronic or a semileptonic final state, and the decay products of the other B in the event are analyzed for consistency with a B(-) --> tau(-)nu(tau) decay. We find no evidence of a signal and set an upper limit on the branching fraction of B(B(-) --> tau(-) nu(tau)) < 4.2 x 10(-4) at the 90% confidence level.

  1. CP violation in Semi-Leptonic {tau} decays

    SciTech Connect

    Delepine, David

    2007-06-19

    We study CP violation in semi-leptonic {tau} decays and we determine the conditions necessary to be able to define a observable CP asymmetry. We apply these conditions in both models, the standard model for the electroweak interactions and its supersymmetric extensions. In the first case, the leading order contribution to the direct CP asymmetry in {tau}{+-} {yields} K{+-}{pi}0{nu}{tau} decay rates is evaluated. In the second case,we compute the SUSY effective hamiltonian that describes the |{delta}S| = 1 semileptonic decays of tau leptons. We show that SUSY contributions may enhance the CP asymmetry of {tau} {yields} K{pi}{nu}{tau} decays by several orders of magnitude compared to the standard model expectations.

  2. Human protein tau represses DNA replication in vitro.

    PubMed

    Li, Wen; Wang, Xing Sheng; Qu, M H; Liu, Ying; He, Rong Qiao

    2005-11-30

    Here, in the experiments of both PCR and real-time PCR, a repression of DNA amplification was observed in the presence of protein tau. Furthermore, a strong repression appeared when an in vitro DNA replication assay was performed at the physiological temperature (37 degrees C). The incorporation of dNTP was markedly decreased to approximately 12% of control by the presence of tau23 and to approximately 15% by tau40. In the competitive experiments, the PCR product could be restored when the competitor DNA was added, indicating that the association of tau with the template gave rise to the repression. However, tau did not repress the yield of RNA in transcription, suggesting that tau was replaced or ejected from the template by the elongating T7 RNA polymerase.

  3. PET Imaging of Tau Deposition in the Aging Human Brain

    PubMed Central

    Schonhaut, Daniel R.; O’Neil, James P.; Janabi, Mustafa; Ossenkoppele, Rik; Baker, Suzanne L.; Vogel, Jacob W.; Faria, Jamie; Schwimmer, Henry D.; Rabinovici, Gil D.; Jagust, William J.

    2016-01-01

    SUMMARY Tau pathology is a hallmark of Alzheimer’s disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent 18F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid, and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition. PMID:26938442

  4. Resonance Effective Theory Approach to {tau} {yields} 3{pi}{nu}{tau} Decays

    SciTech Connect

    Gomez Dumm, D.; Pich, A.; Portoles, J.

    2004-12-02

    The decays {tau} {yields} 3{pi}{nu}{tau} are analyzed in the framework of the resonance effective theory of QCD, We derive the effective chiral Lagrangian relevant for the evaluation of the hadronic axial-vector current, taking into account the constraints imposed by QCD on the high energy asymptotic behaviour. Then we fit the unknown parameters to the spectral function and branching ratio measured by ALEPH, showing that the theory is in good agreement with experimental data. A detailed description of the work sketched here can be found.

  5. Alpha Blockers

    MedlinePlus

    ... conditions such as high blood pressure and benign prostatic hyperplasia. Find out more about this class of medication. ... these conditions: High blood pressure Enlarged prostate (benign prostatic hyperplasia) Though alpha blockers are commonly used to treat ...

  6. Alpha fetoprotein

    MedlinePlus

    ... Alpha fetoprotein - series References Cunningham FG, Leveno KJ, Bloom SL, et al. Prenatal diagnosis and fetal therapy. In: Cunningham FG, Leveno KJ, Bloom SL, et al, eds. Williams Obstetrics . 23rd ed. ...

  7. Alpha Thalassemia

    MedlinePlus

    ... an apparently normal individual has a child with hemoglobin H disease or alpha thalassemia minor. It can ... gene on one chromosome 25% 25% 25% 25% hemoglobin H disease there is a 25% chance with ...

  8. The Relationship between Teacher Training, Intervention Strategies, and Students' Academic Achievement in the Classroom with K-5 ADHD Students

    ERIC Educational Resources Information Center

    Cooper, Nancy A.

    2014-01-01

    The primary intent of this study was to explore the effect between teachers' training, intervention strategies, and the academic achievement of K-5 ADHD students. The study design employed a mixed research design. The quantitative method focused on collecting data from certified regular and special-education teachers. Additionally, effects were…

  9. Exploring the World of Animals: Linking Fiction to Nonfiction. Literature Bridges to Science Series. Grades K-5.

    ERIC Educational Resources Information Center

    Perry, Phyllis J.

    This teacher resource book, designed to encourage student interest and build learning across the curriculum in grades K-5, is based on the theme of animals. Resource lists and activities in the book focus on the following sections: (1) animals as pets; (2) animals on the farm; (3) animals in the woods; and (4) animals in the wild. Each section…

  10. The Positive Impact of World Language Study on Special Needs K-5 Children: A Mixed Methodology Research Study

    ERIC Educational Resources Information Center

    Davis-Wiley, Patricia; Miller, Roy V.

    2010-01-01

    The present research study was conducted to explore how structured Spanish instruction (30 minutes, twice a week, for a semester) impacts the level of class participation and on-task behavior and the reading fluency rate of a group of self-contained, special needs, elementary school children (grades K-5). Data for this mixed methodology study were…

  11. Moving the School and Dancing Education: Case Study Research of K-5 Students' Experiences in a Dance Residency

    ERIC Educational Resources Information Center

    Leonard, Alison E.

    2012-01-01

    This dissertation chronicles the qualitative case study of a dance artist-in-residence at a diverse and inclusive K-5 school in an urban district, integrating science, social studies, physical education, music, and visual arts school curriculum and culminating in two public performances. This study focused on how students made meaning through this…

  12. Examining the Internal Structure of the easyCBM Reading Measures, Grades K-5. Technical Report #1302

    ERIC Educational Resources Information Center

    Alonzo, Julie; Park, Bitnara Jasmine; Tindal, Gerald

    2013-01-01

    In this technical report, we describe a study examining the internal structures of the easyCBM reading measures, Grades K-5. Data were gathered from a convenience sample of 114 Kindergarten students, 43 first graders, 82 second graders, 100 third graders, 109 fourth graders, and 71 fifth graders attending schools in Oregon, Georgia, South…

  13. Global Conformation of Tau Protein Mapped by Raman Spectroscopy.

    PubMed

    Gorantla, Nalini Vijay; Khandelwal, Puneet; Poddar, Pankaj; Chinnathambi, Subashchandrabose

    2017-01-01

    Alzheimer's disease (AD) is one of the neurodegenerative disease characterized by progressive neuronal loss in the brain. Its two major hallmarks are extracellular senile plaques and intracellular neurofibrillary tangles (NFTs), formed by aggregation of amyloid β-42 (Aβ-42) and Tau protein respectively. Aβ-42 is a transmembrane protein, which is produced after the sequential action of β- and γ-secretases, thus obtained peptide is released extracellularly and gets deposited on the neuron forming senile plaques. NFTs are composed of microtubule-associated protein-Tau (MAPT). Tau protein's major function is to stabilize the microtubule that provides a track on which the cargo proteins are shuttled and the stabilized microtubule also maintains shape and integrity of the neuronal cell. Tau protein is subjected to various modifications such as phosphorylation, ubiquitination, glycation, acetylation, truncation, glycosylation, deamination, and oxidation; these modifications ultimately lead to its aggregation. Phosphorylation is the major modification and is extensively studied with respect to Tau protein. Tau protein, however, undergoes certain level of phosphorylation and dephosphorylation, which regulates its affinity for microtubule and ultimately leading to microtubule assembly and disassembly. Our main aim was to study the native state of longest isoform of Tau (hTau40WT-4R2N) and its shortest isoform, (hTau23WT-3R0N), at various temperatures such as 10, 25, and 37 °C. Raman spectroscopic results suggested that the proportion of random coils or unordered structure depends on the temperature of the protein environment. Upon increase in the temperature from 10 to 37 °C, the proportion of random coils or unordered structures increased in the case of hTau40WT. However, we did not find a significant effect of temperature on the structure of hTau23WT. This current approach enables one to analyze the global conformation of soluble Tau in solution.

  14. Robust Coefficients Alpha and Omega and Confidence Intervals with Outlying Observations and Missing Data: Methods and Software

    ERIC Educational Resources Information Center

    Zhang, Zhiyong; Yuan, Ke-Hai

    2016-01-01

    Cronbach's coefficient alpha is a widely used reliability measure in social, behavioral, and education sciences. It is reported in nearly every study that involves measuring a construct through multiple items. With non-tau-equivalent items, McDonald's omega has been used as a popular alternative to alpha in the literature. Traditional estimation…

  15. NMR Meets Tau: Insights into Its Function and Pathology

    PubMed Central

    Lippens, Guy; Landrieu, Isabelle; Smet, Caroline; Huvent, Isabelle; Gandhi, Neha S.; Gigant, Benoît; Despres, Clément; Qi, Haoling; Lopez, Juan

    2016-01-01

    In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same samples. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function. PMID:27338491

  16. Updated measurement of the tau lifetime at SLD

    SciTech Connect

    1996-07-23

    We present an updated measurement of the tau lifetime at SLD. 4316 {tau}-pair events, selected from a 150k Z{sup 0} data sample, are analyzed using three techniques: decay length, impact parameter, and impact parameter difference methods. The measurement benefits from the small and stable interaction region at the SLC and the precision CCD pixel vertex detector of the SLD. The combined result is: {tau}{sub {tau}} = 288.1 {+-} 6.1(stat) {+-} 3.3(syst) fs.

  17. Connecting the Dots Between Tau Dysfunction and Neurodegeneration

    PubMed Central

    Frost, Bess; Götz, Jürgen; Feany, Mel B.

    2014-01-01

    Tauopathies are devastating and ultimately fatal neurodegenerative diseases, which are histopathologically defined by insoluble filamentous deposits of abnormally phosphorylated tau protein within neurons and glia. Identifying the causes of abnormal tau phosphorylation and subsequent aggregation has been the focus of much research, and is currently a major target for the development of therapeutic interventions for tauopathies, including Alzheimer’s disease. Recently much has been learned about the sequence of events that lead from tau dysfunction to neuronal death. This review focuses on the cascade of events that are catalyzed by pathological tau, and highlights current and potential therapeutic strategies to target this pathway. PMID:25172552

  18. Cellular factors modulating the mechanism of tau protein aggregation

    PubMed Central

    Fontaine, Sarah N.; Sabbagh, Jonathan J.; Baker, Jeremy; Martinez-Licha, Carlos R.; Darling, April

    2015-01-01

    Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer’s disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer’s disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones. PMID:25666877

  19. Bovine somatotropin attenuates phorbol ester-induced prostaglandin F2alpha production in bovine endometrial cells.

    PubMed

    Badinga, L; Guzeloglu, A; Thatcher, W W

    2002-03-01

    The recent observation that bovine somatotropin (bST) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone (GH) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle. The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester-induced prostaglandin F2alpha (PGF2alpha) production in cultured bovine endometrial (BEND) cells. Serum-deprived BEND cells were incubated with or without recombinant bovine GH (rbGH), insulin-like growth factor (IGF)-I, recombinant bovine interferon (rbIFN)-tau or a combination of rbGH + rbIFN-tau for 3 h and then treated with phorbol 12,13-dibutyrate (PDBu) for an additional 6 h. Exogenous PDBu increased PGF2alpha secretion and steady-state levels of COX-2 mRNA within 3 h. Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu, whereas cotreatment with IGF-I amplified PDBu induction of PGF2alpha. Preincubation of cell monolayers with rbIFN-tau suppressed PGF2alpha and COX-2 mRNA responses to PDBu. Inhibitory effects of rbGH and rbIFN-tau on PDBu-induced PGF2alpha production were additive. Results provide the first direct evidence that supplemental bST may interact with conceptus-secreted IFN-tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy.

  20. Presynaptic localization of GluK5 in rod photoreceptors suggests a novel function of high affinity glutamate receptors in the mammalian retina

    PubMed Central

    Frotscher, Michael

    2017-01-01

    Kainate receptors mediate glutamatergic signaling through both pre- and presynaptic receptors. Here, we studied the expression of the high affinity kainate receptor GluK5 in the mouse retina. Double-immunofluoresence labeling and electron microscopic analysis revealed a presynaptic localization of GluK5 in the outer plexiform layer. Unexpectedly, we found GluK5 almost exclusively localized to the presynaptic ribbon of photoreceptor terminals. Moreover, in GluK5-deficient mutant mice the structural integrity of synaptic ribbons was severely altered pointing to a novel function of GluK5 in organizing synaptic ribbons in the presynaptic terminals of rod photoreceptors. PMID:28235022

  1. Discoveries of tau, abnormally hyperphosphorylated tau and others of neurofibrillary degeneration: a personal historical perspective.

    PubMed

    Iqbal, Khalid; Grundke-Iqbal, Inge

    2006-01-01

    Alzheimer disease was described by Alois Alzheimer in 1907, but it was not until approximately 60-70 years later that any new significant developments were reported on the pathology of this disease. The discoveries that laid down the foundation for the exciting research that has been carried out during the last approximately 20 years and that have significantly enhanced our understanding of the disease are the ultrastructure of neurofibrillary tangles and neuritic (senile) plaques, the clinical-pathological correlation of these lesions to the presence of dementia, and the bulk isolation and protein composition of paired helical filaments and plaque amyloid. We discovered tau as the major protein subunit of paired helical filaments/neurofibrillary tangles, the abnormal hyperphosphorylation of this protein in this lesion and in Alzheimer brain cytosol and the gain of toxic function by the cytosolic abnormally hyperphosphorylated tau in Alzheimer brain. Here we present a personal historical account of the work in our laboratories that led, in 1986, to the discoveries of tau and its abnormal hyperphosphorylation in paired helical filaments and Alzheimer brain cytosol. This article also describes several major findings which subsequently resulted from the abnormal hyperphosphorylation of tau and in a large part account for the current understanding of the role of this lesion in Alzheimer disease and other tauopathies.

  2. Mobility and subcellular localization of endogenous, gene-edited Tau differs from that of over-expressed human wild-type and P301L mutant Tau

    PubMed Central

    Di Xia; Gutmann, Julia M.; Götz, Jürgen

    2016-01-01

    Alzheimer’s disease (AD) and a subset of frontotemporal dementia termed FTLD-Tau are characterized by a massive, yet incompletely characterized and understood redistribution of Tau. To establish a framework for understanding this pathology, we used the genome-editing tool TALEN and generated Tau-mEOS2 knock-in mice to determine the mobility and subcellular localization of endogenous Tau in hippocampal cultures. We analysed Tau in axons, dendrites and spines at three stages of maturation using live-cell imaging, photo-conversion and FRAP assays. Tau-mEOS2 cultures were compared with those over-expressing EGFP-tagged forms of human wild-type (hWT-Tau) and P301L mutant Tau (hP301L-Tau), modelling Tau accumulation in AD and FTLD-Tau, respectively. In developing neurons, Tau-mEOS2 followed a proximo-distal gradient in axons and a subcellular distribution similar to that of endogenous Tau in neurons obtained from wild-type mice, which were abolished, when either hWT-Tau or hP301L-Tau was over-expressed. For the three conditions, FRAP analysis revealed a similar mobility in dendrites compared with axons; however, Tau-mEOS2 was less mobile than hWT-Tau and hP301L-Tau and the mobile fraction was smaller, possibly reflecting less efficient microtubule binding of Tau when over-expressed. Together, our study presents Tau-mEOS2 mice as a novel tool for the study of Tau in a physiological and a pathological context. PMID:27378256

  3. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers.

    PubMed

    Smith, Ruben; Puschmann, Andreas; Schöll, Michael; Ohlsson, Tomas; van Swieten, John; Honer, Michael; Englund, Elisabet; Hansson, Oskar

    2016-09-01

    Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.

  4. Constraining new interactions with leptonic {tau} decays

    SciTech Connect

    Pich, A.; Silva, J.P.

    1995-10-01

    The recent measurements of the Michel parameters in {tau} decays enable, for the first time, a thorough analysis of the leptonic sector. In general, in models beyond the standard model, these parameters will be altered through changes in the {ital W} and {ital Z} couplings, and/or through interactions mediated by new gauge bosons. We perform a complete, model-independent analysis of the constraints imposed by the present data on such boson-mediated interactions, and point out the existence of useful relations among the couplings.

  5. Proceedings, High-Precision $\\alpha_s$ Measurements from LHC to FCC-ee

    SciTech Connect

    d'Enterria, David; Skands, Peter Z.

    2015-01-01

    This document provides a writeup of all contributions to the workshop on "High precision measurements of $\\alpha_s$: From LHC to FCC-ee" held at CERN, Oct. 12--13, 2015. The workshop explored in depth the latest developments on the determination of the QCD coupling $\\alpha_s$ from 15 methods where high precision measurements are (or will be) available. Those include low-energy observables: (i) lattice QCD, (ii) pion decay factor, (iii) quarkonia and (iv) $\\tau$ decays, (v) soft parton-to-hadron fragmentation functions, as well as high-energy observables: (vi) global fits of parton distribution functions, (vii) hard parton-to-hadron fragmentation functions, (viii) jets in $e^\\pm$p DIS and $\\gamma$-p photoproduction, (ix) photon structure function in $\\gamma$-$\\gamma$, (x) event shapes and (xi) jet cross sections in $e^+e^-$ collisions, (xii) W boson and (xiii) Z boson decays, and (xiv) jets and (xv) top-quark cross sections in proton-(anti)proton collisions. The current status of the theoretical and experimental uncertainties associated to each extraction method, the improvements expected from LHC data in the coming years, and future perspectives achievable in $e^+e^-$ collisions at the Future Circular Collider (FCC-ee) with $\\cal{O}$(1--100 ab$^{-1}$) integrated luminosities yielding 10$^{12}$ Z bosons and jets, and 10$^{8}$ W bosons and $\\tau$ leptons, are thoroughly reviewed. The current uncertainty of the (preliminary) 2015 strong coupling world-average value, $\\alpha_s(m_Z)$ = 0.1177 $\\pm$ 0.0013, is about 1\\%. Some participants believed this may be reduced by a factor of three in the near future by including novel high-precision observables, although this opinion was not universally shared. At the FCC-ee facility, a factor of ten reduction in the $\\alpha_s$ uncertainty should be possible, mostly thanks to the huge Z and W data samples available.

  6. Studies of tau- to h- h- h+ nu and tau- to K- pi0 nu Decays at BaBar

    SciTech Connect

    Nugent, I.M.; /Victoria U.

    2007-10-24

    We present preliminary inclusive branching fraction measurements of {tau}{sup -} {yields} h{sup -}h{sup -}h{sup +}{nu} (h = {pi} or K) and {tau}{sup -} K{sup -}{pi}{sup 0}{nu} decay modes using a sample of {tau}-pair events collected by the BABAR detector at the SLAC PEP-II asymmetric e{sup +}e{sup -} storage ring. The branching fractions of {tau}{sup -} {yields} {pi}{sup -}{pi}{sup -}{pi}{sup +}, {tau}{sup -} {yields} K{sup -}{pi}{sup -}{pi}{sup +}{nu}, and {tau}{sup -} {yields} K{sup -}{pi}{sup -}K{sup +}{nu} are measured with higher precision than previously published results and the inclusive branching fraction {tau}{sup -} {yields} K{sup -}K{sup -}K{sup +}{nu} is measured for the first time. In addition, the first measurement of the branching fraction {tau}{sup -} {yields} {pi}{sup -}{phi}{nu} and the measurement of the branching fraction {tau}{sup -} {yields} K{sup -}{phi}{nu} are determined by means of a binned maximum likelihood fit to the K{sup +}K{sup -} invariant mass distribution. These branching fractions are extracted by means of a migration matrix that accounts for the cross contamination between the {tau}{sup -} {yields} h{sup -}h{sup -}h{sup +}{nu} modes. The preliminary {tau}{sup -} {yields} K{sup -}{pi}{sup 0}{nu} branching fraction and invariant mass distributions are also presented in this paper.

  7. Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation.

    PubMed

    Li, Xiao-Hong; Xie, Jia-Zhao; Jiang, Xia; Lv, Bing-Ling; Cheng, Xiang-Shu; Du, Lai-Ling; Zhang, Jia-Yu; Wang, Jian-Zhi; Zhou, Xin-Wen

    2012-12-01

    The hyperphosphorylated tau is a major protein component of neurofibrillary tangle, which is one of hallmarks of Alzheimer's disease (AD). While the level of methylglyoxal (MG) is significantly increased in the AD brains, the role of MG in tau phosphorylation is still not reported. Here, we found that MG could induce tau hyperphosphorylation at multiple AD-related sites in neuroblastoma 2a cells under maintaining normal cell viability. MG treatment increased the level of advanced glycation end products (AGEs) and the receptor of AGEs (RAGE). Glycogen synthesis kinase-3β (GSK-3β) and p38 MAPK were activated, whereas the level and activity of JNK, Erk1/2, cdk5, and PP2A were not altered after MG treatment. Simultaneous inhibition of GSK-3β or p38 attenuated the MG-induced tau hyperphosphorylation. Aminoguanidine, a blocker of AGEs formation, could effectively reverse the MG-induced tau hyperphosphorylation. These data suggest that MG induces AD-like tau hyperphosphorylation through AGEs formation involving RAGE up-regulation and GSK-3β activation and p38 activation is also partially involved in MG-induced tau hyperphosphorylation. Thus, targeting MG may be a promising therapeutic strategy to prevent AD-like tau hyperphosphorylation.

  8. Identification of nuclear. tau. isoforms in human neuroblastoma cells

    SciTech Connect

    Loomis, P.A.; Howard, T.H.; Castleberry, R.P.; Binder, L.I. )

    1990-11-01

    The {tau} proteins have been reported only in association with microtubules and with ribosomes in situ, in the normal central nervous system. In addition, {tau} has been shown to be an integral component of paired helical filaments, the principal constituent of the neurofibrillary tangles found in brains of patients with Alzheimer's disease and of most aged individuals with Down syndrome (trisomy 21). The authors report here the localization of the well-characterized Tau-1 monoclonal antibody to the nucleolar organizer regions of the acrocentric chromosomes and to their interphase counterpart, the fibrillar component of the nucleolus, in human neuroblastoma cells. Similar localization to the nucleolar organizer regions was also observed in other human cell lines and in one monkey kidney cell line but was not seen in non-primate species. Immunochemically, they further demonstrated the existence of the entire {tau} molecule in the isolated nuclei of neuroblastoma cells. Nuclear {tau} proteins, like the {tau} proteins of the paired helical filaments, cannot be extracted in standard SDS-containing electrophoresis sample buffer but require pretreatment with formic acid prior to immunoblot analysis. This work indicates that {tau} may function in processes not directly associated with microtubules and that highly insoluble complexes of {tau} may also play a role in normal cellular physiology.

  9. Importance of precision measurements in the tau sector

    SciTech Connect

    Pich, A.

    1996-01-01

    {tau} decays provide a powerful tool to test the structure of the weak currents and the universality of their couplings to the {ital W} boson. The constraints implied by present data and the possible improvements at the {tau}cF are analyzed. {copyright} {ital 1996 American Institute of Physics.}

  10. Tau and neurodegenerative disease: the story so far.

    PubMed

    Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2016-01-01

    In 1975, tau protein was isolated as a microtubule-associated factor from the porcine brain. In the previous year, a paired helical filament (PHF) protein had been identified in neurofibrillary tangles in the brains of individuals with Alzheimer disease (AD), but it was not until 1986 that the PHF protein and tau were discovered to be one and the same. In the AD brain, tau was found to be abnormally hyperphosphorylated, and it inhibited rather than promoted in vitro microtubule assembly. Almost 80 disease-causing exonic missense and intronic silent mutations in the tau gene have been found in familial cases of frontotemporal dementia but, to date, no such mutation has been found in AD. The first phase I clinical trial of an active tau immunization vaccine in patients with AD was recently completed. Assays for tau levels in cerebrospinal fluid and plasma are now available, and tau radiotracers for PET are under development. In this article, we provide an overview of the pivotal discoveries in the tau research field over the past 40 years. We also review the current status of the field, including disease mechanisms and therapeutic approaches.

  11. Widespread tau seeding activity at early Braak stages.

    PubMed

    Furman, Jennifer L; Vaquer-Alicea, Jaime; White, Charles L; Cairns, Nigel J; Nelson, Peter T; Diamond, Marc I

    2017-01-01

    Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer's disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also develop seeding activity prior to accumulation of phospho-tau. We measured tau seeding activity across four brain regions (hippocampus, frontal lobe, parietal lobe, and cerebellum) in 104 fresh-frozen human AD brain samples from all Braak stages. We observed widespread seeding activity, notably in regions predicted to be free of phospho-tau deposition, and in detergent-insoluble fractions that lacked tau detectable by ELISA. Seeding activity correlated positively with Braak stage and negatively with MMSE. Our results are consistent with early transcellular propagation of tau seeds that triggers subsequent development of neuropathology. The FRET-based seeding assay may also complement standard neuropathological classification of tauopathies.

  12. Dimethyl sulfoxide induces both direct and indirect tau hyperphosphorylation.

    PubMed

    Julien, Carl; Marcouiller, François; Bretteville, Alexis; El Khoury, Noura B; Baillargeon, Joanie; Hébert, Sébastien S; Planel, Emmanuel

    2012-01-01

    Dimethyl sulfoxide (DMSO) is widely used as a solvent or vehicle for biological studies, and for treatment of specific disorders, including traumatic brain injury and several forms of amyloidosis. As Alzheimer's disease (AD) brains are characterized by deposits of β-amyloid peptides, it has been suggested that DMSO could be used as a treatment for this devastating disease. AD brains are also characterized by aggregates of hyperphosphorylated tau protein, but the effect of DMSO on tau phosphorylation is unknown. We thus investigated the impact of DMSO on tau phosphorylation in vitro and in vivo. One hour following intraperitoneal administration of 1 or 2 ml/kg DMSO in mice, no change was observed in tau phosphorylation. However, at 4 ml/kg, tau was hyperphosphorylated at AT8 (Ser(202)/Thr(205)), PHF-1 (Ser(396)/Ser(404)) and AT180 (Thr(231)) epitopes. At this dose, we also noticed that the animals were hypothermic. When the mice were maintained normothermic, the effect of 4 ml/kg DMSO on tau hyperphosphorylation was prevented. On the other hand, in SH-SY5Y cells, 0.1% DMSO induced tau hyperphosphorylation at AT8 and AT180 phosphoepitopes in normothermic conditions. Globally, these findings demonstrate that DMSO can induce tau hyperphosphorylation indirectly via hypothermia in vivo, and directly in vitro. These data should caution researchers working with DMSO as it can induce artifactual results both in vivo and in vitro.

  13. Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters

    PubMed Central

    Goudarzi, Afsaneh; Zhang, Di; Huang, He; Barral, Sophie; Kwon, Oh Kwang; Qi, Shankang; Tang, Zhanyun; Buchou, Thierry; Vitte, Anne-Laure; He, Tieming; Cheng, Zhongyi; Montellier, Emilie; Gaucher, Jonathan; Curtet, Sandrine; Debernardi, Alexandra; Charbonnier, Guillaume; Puthier, Denis; Petosa, Carlo; Panne, Daniel; Rousseaux, Sophie; Roeder, Robert G.; Zhao, Yingming; Khochbin, Saadi

    2016-01-01

    Summary Recently discovered histone lysine acylation marks increase the functional diversity of nucleosomes well beyond acetylation. Here, we focus on histone butyrylation in the context of sperm cell differentiation. Specifically, we investigate the butyrylation of histone H4 lysine 5 and 8 at gene promoters where acetylation guides the binding of Brdt, a bromodomain-containing protein, thereby mediating stage-specific gene expression programs and post-meiotic chromatin reorganization. Genome-wide mapping data show that highly active Brdt-bound gene promoters systematically harbor competing histone acetylation and butyrylation marks at H4 K5 and H4 K8. Despite acting as a direct stimulator of transcription, histone butyrylation competes with acetylation, especially at H4 K5, to prevent Brdt binding. Additionally, H4 K5K8 butyrylation also marks retarded histone removal during late spermatogenesis. Hence, alternating H4 acetylation and butyrylation, while sustaining direct gene activation and dynamic bromodomain binding, could impact the final male epigenome features. PMID:27105113

  14. Anticipating arrival: is the tau margin a specious theory?

    PubMed

    Wann, J P

    1996-08-01

    A critical review is presented of previous studies that have examined the use of the tau margin (tau m) in the temporal judgment of arrival in natural contexts. This body of evidence is frequently cited as providing strong support for the use of Tau m for interceptive timing. Critical flaws are demonstrated in either the analysis or interpretation of many of these studies. It is suggested that temporal control in a number of these experiments could have been effected using a relative distance estimate (zeta ratio). Results are also presented and discussed that conflict with the tau m control hypothesis. It is concluded that although the tau m hypothesis provides an appealing account of interceptive timing, its broad acceptance is unwarranted on the evidence available.

  15. Period Change and Evolutionary Status of SW Tau

    NASA Astrophysics Data System (ADS)

    Devlen, Ahmet; Acar, Mert

    2017-03-01

    In this work, the relation between the period change and evolutionary status of SW Tau, a Type II Cepheid variable, is examined. An (O–C) analysis of the times of maxima of SW Tau has been undertaken to determine this relation. SW Tau has the characteristic light curve shape of BL Her type stars. By taking into consideration SW Tau’s well-defined period decrease, obtained from the photometric observations, its position on the HR diagram in accordance with evolutionary models, and its chemical composition, we demonstrate that SW Tau is a Cepheid crossing the instability strip for the fourth time. SW Tau could be interpreted as being an early AGB star on the blueward evolutionary phase during shell helium burning.

  16. 14-3-3ζ Mediates Tau Aggregation in Human Neuroblastoma M17 Cells.

    PubMed

    Li, Tong; Paudel, Hemant K

    2016-01-01

    Microtubule-associated protein tau is the major component of paired helical filaments (PHFs) associated with the neuropathology of Alzheimer's disease (AD). Tau in the normal brain binds and stabilizes microtubules. Tau isolated from PHFs is hyperphosphorylated, which prevents it from binding to microtubules. Tau phosphorylation has been suggested to be involved in the development of NFT pathology in the AD brain. Recently, we showed that 14-3-3ζ is bound to tau in the PHFs and when incubated in vitro with 14-3-3ζ, tau formed amorphous aggregates, single-stranded straight filaments, double stranded ribbon-like filaments and PHF-like filaments that displayed close resemblance with corresponding ultrastructures of AD brain. Surprisingly however, phosphorylated and non-phosphorylated tau aggregated in a similar manner, indicating that tau phosphorylation does not affect in vitro tau aggregation (Qureshi et al (2013) Biochemistry 52, 6445-6455). In this study, we have examined the role of tau phosphorylation in tau aggregation in cellular level. We have found that in human M17 neuroblastoma cells, tau phosphorylation by GSK3β or PKA does not cause tau aggregation, but promotes 14-3-3ζ-induced tau aggregation by destabilizing microtubules. Microtubule disrupting drugs also promoted 14-3-3ζ-induced tau aggregation without changing tau phosphorylation in M17 cell. In vitro, when incubated with 14-3-3ζ and microtubules, nonphosphorylated tau bound to microtubules and did not aggregate. Phosphorylated tau on the other hand did not bind to microtubules and aggregated. Our data indicate that microtubule-bound tau is resistant to 14-3-3ζ-induced tau aggregation and suggest that tau phosphorylation promotes tau aggregation in the brain by detaching tau from microtubules and thus making it accessible to 14-3-3ζ.

  17. 14-3-3ζ Mediates Tau Aggregation in Human Neuroblastoma M17 Cells

    PubMed Central

    Li, Tong; Paudel, Hemant K.

    2016-01-01

    Microtubule-associated protein tau is the major component of paired helical filaments (PHFs) associated with the neuropathology of Alzheimer’s disease (AD). Tau in the normal brain binds and stabilizes microtubules. Tau isolated from PHFs is hyperphosphorylated, which prevents it from binding to microtubules. Tau phosphorylation has been suggested to be involved in the development of NFT pathology in the AD brain. Recently, we showed that 14-3-3ζ is bound to tau in the PHFs and when incubated in vitro with 14-3-3ζ, tau formed amorphous aggregates, single-stranded straight filaments, double stranded ribbon-like filaments and PHF-like filaments that displayed close resemblance with corresponding ultrastructures of AD brain. Surprisingly however, phosphorylated and non-phosphorylated tau aggregated in a similar manner, indicating that tau phosphorylation does not affect in vitro tau aggregation (Qureshi et al (2013) Biochemistry 52, 6445–6455). In this study, we have examined the role of tau phosphorylation in tau aggregation in cellular level. We have found that in human M17 neuroblastoma cells, tau phosphorylation by GSK3β or PKA does not cause tau aggregation, but promotes 14-3-3ζ-induced tau aggregation by destabilizing microtubules. Microtubule disrupting drugs also promoted 14-3-3ζ-induced tau aggregation without changing tau phosphorylation in M17 cell. In vitro, when incubated with 14-3-3ζ and microtubules, nonphosphorylated tau bound to microtubules and did not aggregate. Phosphorylated tau on the other hand did not bind to microtubules and aggregated. Our data indicate that microtubule-bound tau is resistant to 14-3-3ζ-induced tau aggregation and suggest that tau phosphorylation promotes tau aggregation in the brain by detaching tau from microtubules and thus making it accessible to 14-3-3ζ. PMID:27548710

  18. Mechanisms of tau and Aβ-induced excitotoxicity.

    PubMed

    Pallo, Susanne P; DiMaio, John; Cook, Alexis; Nilsson, Bradley; Johnson, Gail V W

    2016-03-01

    Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer׳s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau(-/-)) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca(2+) influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca(2+) influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca(2+) influx. While Aβ biphasically modulated the KA-induced Cacyt(2+) responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca(2+) influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 min) enhanced KA-induced Ca(2+) influx, while chronic Aβ (24 h) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca(2+) influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1mGluR activation.

  19. VMD approach to {tau}{sup -}{yields}({omega},{phi}){pi}{sup -}{nu}{sub {tau}} decays

    SciTech Connect

    Falcon, D. A. Lopez; Castro, G. Lopez

    1997-03-15

    We give a description of {tau}{sup -}{yields}({omega},{phi}){pi}{sup -}{nu}{sub {tau}} decays in the approach of the vector-meson dominance (VMD) model and compare our results with the conserved vector current (CVC) predictions and experimental data.

  20. Apolipoprotein E genotyping and cerebrospinal fluid tau protein: implications for the clinical diagnosis of Alzheimer's disease.

    PubMed

    Arai, H; Higuchi, S; Sasaki, H

    1997-01-01

    Apolipoprotein E (ApoE) genotyping was conducted in sporadic Alzheimer's disease (AD, n = 91) as well as in other dementing disorders including Parkinson's disease (PD, n = 73), autopsy-confirmed diffuse Lewy body disease (DLBD, n = 16), progressive supranuclear palsy (n = 13), vascular dementia (n = 55), alcoholic dementia (n =25) and normal control subjects (n = 77). ApoE epsilon 4 allele frequency was significantly higher in AD (33.5%, p < 0.001), DLBD (40.6%, p < 0.001) and demented PD (29.4%, p < 0.05) compared to that in normal controls (11.7%). The association of the ApoE epsilon 4 allele with AD was more pronounced in early-onset AD (46.4%) than in late-onset AD (27.8%). 46% of the AD individuals developed AD without association to ApoE epsilon 4, and epsilon 4 homozygotes were found not only in AD, but also in many of other dementing disorders. These results suggest that ApoE genotyping cannot provide certainty about the presence of absence of AD, and that it should be used as an adjunct to other diagnostic tests for AD. On the other hand, cerebrospinal fluid (CSF) tau levels were significantly elevated (p < 0.0001) in AD (78.0 +/- 44.2 pg/ml) compared to those in normal controls (10.6 +/- 8.6 pg/ml). The specificity and the sensitivity of distinguishing AD from normal controls was 95.0 and 91.2%, respectively. Elevated CSF-tau levels were also detected in some patients with acute neurological diseases including meningoencephalitis, Creutzfeld-Jacob disease, normal pressure hydrocephalus and vitamin B12 deficiency encephalopathy. Increased CSF-tau levels in AD were found regardless of the age at onset, clinical stage, ApoE genotype, alpha 1-antichymotrypsin genotype, and presenilin-1 genotype. The CSF-tau levels continued to be abnormal during the progression of AD. These results suggest that CSF-tau serves as an unequivocal and reliable biological marker to aid in the clinical diagnosis of AD.

  1. Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis.

    PubMed

    Rostasy, Kevin; Withut, Esther; Pohl, Daniela; Lange, Peter; Ciesielcyk, Barbara; Diem, Ricarda; Gärtner, Jutta; Otto, Markus

    2005-10-01

    Axonal injury and glial activation are an early neuropathologic event in adults with multiple sclerosis. To investigate whether markers of axonal injury and glial activation are already elevated in the cerebrospinal fluid of children with multiple sclerosis, we studied the cerebrospinal fluid of 25 children with multiple sclerosis and 67 controls for the presence of tau, phospho-tau, and S-100B proteins using specific enzyme-linked immunoabsorbent assays. In general, tau, phospho-tau, and S-100B protein levels did not differ significantly between groups. However, in a subgroup of nine children with multiple sclerosis, all of whom had prominent clinical symptoms at the time of lumbar puncture and radiologic disease activity, tau protein levels were significantly elevated when compared with other controls. These data indicate that axonal injury is not restricted to adult multiple sclerosis but can already occur in children with multiple sclerosis.

  2. Hadron structure in {tau}{yields}KK{pi}{nu}{sub {tau}}decays

    SciTech Connect

    Gomez Dumm, D.; Roig, P.; Pich, A.; Portoles, J.

    2010-02-01

    We analyze the hadronization structure of both vector and axial-vector currents leading to {tau}{yields}KK{pi}{nu}{sub {tau}}decays. At leading order in the 1/N{sub C} expansion, and considering only the contribution of the lightest resonances, we work out, within the framework of the resonance chiral Lagrangian, the structure of the local vertices involved in those processes. The couplings in the resonance theory are constrained by imposing the asymptotic behavior of vector and axial-vector spectral functions ruled by QCD. In this way we predict the hadron spectra and conclude that, contrary to previous assertions, the vector contribution dominates by far over the axial-vector one in all KK{pi} charge channels.

  3. Overexpression of Wild-Type Murine Tau Results in Progressive Tauopathy and Neurodegeneration

    PubMed Central

    Adams, Stephanie J.; Crook, Richard J.P.; DeTure, Michael; Randle, Suzanne J.; Innes, Amy E.; Yu, Xin Z.; Lin, Wen-Lang; Dugger, Brittany N.; McBride, Melinda; Hutton, Mike; Dickson, Dennis W.; McGowan, Eileen

    2009-01-01

    Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer’s disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies. PMID:19717642

  4. Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition

    PubMed Central

    2014-01-01

    Introduction Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. Methods We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). Results We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. Conclusion Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology. PMID:24576665

  5. Porcine MAP3K5 analysis: molecular cloning, characterization, tissue expression pattern, and copy number variations associated with residual feed intake.

    PubMed

    Pu, L; Zhang, L C; Zhang, J S; Song, X; Wang, L G; Liang, J; Zhang, Y B; Liu, X; Yan, H; Zhang, T; Yue, J W; Li, N; Wu, Q Q; Wang, L X

    2016-08-12

    Mitogen-activated protein kinase kinase kinase 5 (MAP3K5) is essential for apoptosis, proliferation, differentiation, and immune responses, and is a candidate marker for residual feed intake (RFI) in pig. We cloned the full-length cDNA sequence of porcine MAP3K5 by rapid-amplification of cDNA ends. The 5451-bp gene contains a 5'-untranslated region (UTR) (718 bp), a coding region (3738 bp), and a 3'-UTR (995 bp), and encodes a peptide of 1245 amino acids, which shares 97, 99, 97, 93, 91, and 84% sequence identity with cattle, sheep, human, mouse, chicken, and zebrafish MAP3K5, respectively. The deduced MAP3K5 protein sequence contains two conserved domains: a DUF4071 domain and a protein kinase domain. Phylogenetic analysis showed that porcine MAP3K5 forms a separate branch to vicugna and camel MAP3K5. Tissue expression analysis using real-time quantitative polymerase chain reaction (qRT-PCR) revealed that MAP3K5 was expressed in the heart, liver, spleen, lung, kidney, muscle, fat, pancrea, ileum, and stomach tissues. Copy number variation was detected for porcine MAP3K5 and validated by qRT-PCR. Furthermore, a significant increase in average copy number was detected in the low RFI group when compared to the high RFI group in a Duroc pig population. These results provide useful information regarding the influence of MAP3K5 on RFI in pigs.

  6. Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology.

    PubMed

    Hochgräfe, Katja; Sydow, Astrid; Mandelkow, Eva-Maria

    2013-09-01

    Accumulation of amyloidogenic proteins such as Tau is a hallmark of neurodegenerative diseases including Alzheimer disease and fronto-temporal dementias. To link Tau pathology to cognitive impairments and defects in synaptic plasticity, we created four inducible Tau transgenic mouse models with expression of pro- and anti-aggregant variants of either full-length human Tau (hTau40/ΔK280 and hTau40/ΔK280/PP) or the truncated Tau repeat domain (Tau(RD)/ΔK280 and Tau(RD)/ΔK280/PP). Here we review the histopathological features caused by pro-aggregant Tau, and correlate them with behavioral deficits and impairments in synaptic transmission. Both pro-aggregant Tau variants cause Alzheimer-like features, including synapse loss, mis-localization of Tau into the somatodendritic compartment, conformational changes and hyperphosphorylation. However, there is a clear difference in the extent of Tau aggregation and neurotoxicity. While pro-aggregant full-length hTau40/ΔK280 leads to a 'pre-tangle' pathology, the repeat domain Tau(RD)/ΔK280 causes massive formation of neurofibrillary tangles and neuronal loss in the hippocampus. However, both Tau variants cause co-aggregation of human and mouse Tau and similar functional impairments. Thus, earlier Tau pathological stages and not necessarily neurofibrillary tangles are critical for the development of cognitive malfunctions. Most importantly, memory and synapses recover after switching off expression of pro-aggregant Tau. The rescue of functional impairments correlates with the rescue of most Tau pathological changes and most strikingly the recovery of synapses. This implies that tauopathies as such are reversible, provided that amyloidogenic Tau is removed. Therefore, our Tau transgenic mice may serve as model systems for in vivo validation of therapeutic strategies and drug candidates with regard to cognition and synaptic function.

  7. Activation of human alpha1 and alpha2 homomeric glycine receptors by taurine and GABA.

    PubMed

    De Saint Jan, D; David-Watine, B; Korn, H; Bregestovski, P

    2001-09-15

    1. Two ligand binding alpha subunits, alpha1 and alpha2, of the human (H) glycine receptor (GlyR) are involved at inhibitory synapses in the adult and neonatal spinal cord, respectively. The ability of homomeric alphaH1 and alphaH2 GlyRs to be activated by glycine, taurine and GABA was studied in Xenopus oocytes or in the human embryonic kidney HEK-293 cell line. 2. In outside-out patches from HEK cells, glycine, taurine and GABA activated both GlyRs with the same main unitary conductance, i.e. 85 +/- 3 pS (n = 6) for alphaH1, and 95 +/- 5 pS (n = 4) for alphaH2. 3. The sensitivity of both alphaH1 and alphaH2 GlyRs to glycine was highly variable. In Xenopus oocytes the EC50 for glycine (EC50gly) was between 25 and 280 microM for alphaH1 (n = 44) and between 46 and 541 microM for alphaH2 (n = 52). For both receptors, the highest EC50gly values were found on cells with low maximal glycine responses. 4. The actions of taurine and GABA were dependent on the EC50gly: (i) their EC50 values were linearly correlated to EC50gly, with EC50tau approximately 10 EC50gly and EC50GABA approximately 500-800 EC50gly; (ii) they could act either as full or weak agonists depending on the EC50gly. 5. The Hill coefficient (n(H)) of glycine remained stable regardless of the EC50gly whereas n(H) for taurine decreased with increasing EC50tau. 6. The degree of desensitization, evaluated by fast application of saturating concentrations of agonist on outside-out patches from Xenopus oocytes, was similar for glycine and taurine on both GlyRs and did not exceed 50 %. 7. Our data concerning the variations of EC50gly and the subsequent behaviour of taurine and GABA could be qualitatively described by the simple del Castillo-Katz scheme, assuming that the agonist gating constant varies whereas the binding constants are stable. However, the stability of the Hill coefficient for glycine was not explained by this model, suggesting that other mechanisms are involved in the modulation of EC50.

  8. Deep photospheric flows in Tau Scorpii

    NASA Technical Reports Server (NTRS)

    Smith, M. A.; Karp, A. H.

    1979-01-01

    From analysis of weak, unblended, ultraviolet lines observed in Tau Scorpii by Copernicus, the same line widths and the same slightly blue-depressed wings as found in the upper photospheric lines of the visual region are found. In addition, a radial-velocity discrepancy of about 6 km/s between weak and strong lines in the 1000-1300-A region is found. These results are in quantitative agreement with one another and with the results of the visual region. They imply that a flow of material is present even in the deep photosphere of this star. However, one cannot yet specify the geometry of the flow (outward-radial versus temperature-weighted convection columns). At the least, this flow alters the expected radiation-driven flow solution close to the photosphere. At the most, it could provide the heating of a chromosphere or a corona just outside the photosphere, as required by the imperfect flow model.

  9. CP Violation in Tau to K* Decays

    SciTech Connect

    Hodgkinson, Mark; /Manchester U.

    2006-03-10

    A sample of {tau}{sup {+-}} {yields} K*{sup {+-}} decays with K*{sup {+-}} {yields} K{sub S}{sup 0}{pi}{sup {+-}} and K{sub S}{sup 0} {yields} {pi}{sup +}{pi}{sup -}, using 123.4 fb{sup -1} of data collected by the BaBar detector at the Stanford Linear Accelerator Center, is used to search for a direct CP violation effect in the charged Higgs sector. No evidence of CP violation is found and the imaginary part of the charged Higgs coupling, {l_brace}Im{r_brace}({Lambda}), in the Multi-Higgs-Doublet-Model is found to be at -0.284 < {l_brace}Im{r_brace}({Lambda}) < 0.200 at 90% Confidence Level. In addition the installation of the kk2f Monte Carlo generator into the BaBar software framework is described.

  10. First measurement of sigma (p anti-p ---> Z) . Br (Z ---> tau tau) at s**(1/2) = 1.96- TeV

    SciTech Connect

    Abazov, V.M.; Abbott, B.; Abolins, M.; Acharya, B.S.; Adams, M.; Adams, T.; Agelou, M.; Agram, J.-L.; Ahn, S.H.; Ahsan, M.; Alexeev, G.D.; Alkhazov, G.; Alton, A.; Alverson, G.; Alves, G.A.; Anastasoaie, M.; Andeen, T.; Anderson, S.; Andrieu, B.; Arnoud, Y.; Askew, A.; /Buenos Aires U. /Rio de Janeiro, CBPF /Rio de Janeiro State U. /Sao Paulo, IFT /Alberta U. /Simon Fraser U. /York U., Canada /McGill U. /Beijing, Inst. High Energy Phys. /Andes U., Bogota /Charles U. /Prague, Tech. U. /Prague, Inst. Phys. /San Francisco de Quito U. /Clermont-Ferrand U. /LPSC, Grenoble /Marseille, CPPM /Orsay, LAL /Paris U., VI-VII /DAPNIA, Saclay /Strasbourg, IReS

    2004-12-01

    The authors present a measurement of the cross section for Z production times the branching fraction to {tau} leptons, {sigma} {center_dot} Br(Z {yields} {tau}{sup +}{tau}{sup -}), in p{bar p} collisions at {radical}s = 1.96 TeV in the channel in which one {tau} decays into {mu}{nu}{sub {mu}}{nu}{sub {tau}}, and the other into hadrons + {nu}{sub {tau}} or e{nu}{sub e}{nu}{sub {tau}}. The data sample corresponds to an integrated luminosity of 226 pb{sup -1} collected with the D0 detector at the Fermilab Tevatron collider. The final sample contains 2008 candidate events with an estimated background of 55%. From this they obtain {sigma} {center_dot} Br(Z {yields} {tau}{sup +}{tau}{sup -}) = 237 {+-} 15(stat) {+-} 18(sys) {+-} 15(lum) pb, in agreement with the standard model prediction.

  11. Lepton flavor violating {tau} and B decays and heavy neutrinos

    SciTech Connect

    He Xiaogang

    2004-12-01

    We study lepton flavor violating (LFV) {tau} and B decays in models with heavy neutrinos to constrain the mixing matrix parameters U{sub {tau}}{sub N}. We find that the best current constraints when the heavy neutrinos are purely left handed come from LFV radiative {tau} decay modes. To obtain competitive constraints in LFV B decay, it is necessary to probe b{yields}X{sub s}{tau}{sup {+-}}e{sup {+-}} at the 10{sup -7} level. When the heavy neutrinos have both left- and right-handed couplings, the mixing parameters can be constrained by studying LFV B decay modes and LFV {tau} decay into three charged leptons. We find that the branching ratios B({tau}{sup {+-}}{yields}l{sub 1}{sup {+-}}l{sub 2}{sup {+-}}l{sub 3}{sup {+-}}), B(B{sub s}{yields}{tau}{sup {+-}}e{sup {+-}}) and B(b{yields}X{sub s}l{sub 1}{sup {+-}}l{sub 2}{sup {+-}}) need to be probed at the 10{sup -8} level in order to constrain the mixing parameters beyond what is known from unitarity.

  12. Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

    PubMed Central

    Leroy, Karelle; Bretteville, Alexis; Schindowski, Katharina; Gilissen, Emmanuel; Authelet, Michèle; De Decker, Robert; Yilmaz, Zehra; Buée, Luc; Brion, Jean-Pierre

    2007-01-01

    Neurodegenerative diseases characterized by brain and spinal cord involvement often show widespread accumulations of tau aggregates. We have generated a transgenic mouse line (Tg30tau) expressing in the forebrain and the spinal cord a human tau protein bearing two pathogenic mutations (P301S and G272V). These mice developed age-dependent brain and hippocampal atrophy, central and peripheral axonopathy, progressive motor impairment with neurogenic muscle atrophy, and neurofibrillary tangles and had decreased survival. Axonal spheroids and axonal atrophy developed early before neurofibrillary tangles. Neurofibrillary inclusions developed in neurons at 3 months and were of two types, suggestive of a selective vulnerability of neurons to form different types of fibrillary aggregates. A first type of tau-positive neurofibrillary tangles, more abundant in the forebrain, were composed of ribbon-like 19-nm-wide filaments and twisted paired helical filaments. A second type of tau and neurofilament-positive neurofibrillary tangles, more abundant in the spinal cord and the brainstem, were composed of 10-nm-wide neurofilaments and straight 19-nm filaments. Unbiased stereological analysis indicated that total number of pyramidal neurons and density of neurons in the lumbar spinal cord were not reduced up to 12 months in Tg30tau mice. This Tg30tau model thus provides evidence that axonopathy precedes tangle formation and that both lesions can be dissociated from overt neuronal loss in selected brain areas but not from neuronal dysfunction. PMID:17690183

  13. Measurement of the tau- to eta pi-pi+pi-nu tau Branching Fraction and a Search for a Second-Class Current in the tau- to eta'(958)pi-nu tau Decay

    SciTech Connect

    Aubert, B.; Bona, M.; Boutigny, D.; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Prudent, X.; Tisserand, V.; Zghiche, A.; Garra Tico, J.; Grauges, E.; Lopez, L.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Abrams, G.S.; Battaglia, M.; Brown, David Nathan; Button-Shafer, J.; /LBL, Berkeley /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /Bristol U. /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UCLA /UC, Riverside /UC, San Diego /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /Ferrara U. /Frascati /Genoa U. /Harvard U. /Heidelberg U. /Imperial Coll., London /Iowa U. /Iowa State U. /Johns Hopkins U. /Karlsruhe U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT, LNS /McGill U. /Milan U. /INFN, Milan /Mississippi U. /Montreal U. /Mt. Holyoke Coll. /Naples U. /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /Padua U. /Paris U., VI-VII /Pennsylvania U. /Perugia U. /Pisa U. /Princeton U. /INFN, Rome /Rostock U. /Rutherford /DSM, DAPNIA, Saclay /South Carolina U. /SLAC /Stanford U., Phys. Dept. /SUNY, Albany /Tennessee U. /Texas U. /Texas U., Dallas /Turin U. /INFN, Turin /Trieste U. /Valencia U., IFIC /Victoria U. /Warwick U. /Wisconsin U., Madison /Yale U.

    2008-03-24

    The {tau}{sup -} {yields} {eta}{pi}{sup -}{pi}{sup +}{pi}{sup -}{nu}{sub {tau}} decay with the {eta} {yields} {gamma}{gamma} mode is studied using 384 fb{sup -1} of data collected by the BABAR detector. The branching fraction is measured to be (1.60 {+-} 0.05 {+-} 0.11) x 10{sup -4}. It is found that {tau}{sup -} {yields} f{sub 1}(1285){pi}{sup -} {nu}{sub {tau}} {yields} {eta}{pi}{sup -}{pi}{sup +}{pi}{sup -}{nu}{sub {tau}} is the dominant decay mode with a branching fraction of (1.11 {+-} 0.06 {+-} 0.05) x 10{sup -4}. The first error on the branching fractions is statistical and the second systematic. In addition, a 90% confidence level upper limit on the branching fraction of the {tau}{sup -} {yields} {eta}{prime}(958){pi}{sup -}{nu}{sub {tau}} decay is measured to be 7.2 x 10{sup -6}. This last decay proceeds through a second-class current and is expected to be forbidden in the limit of isospin symmetry.

  14. Effects of macromolecular crowding and osmolyte on human Tau fibrillation.

    PubMed

    Wu, Yingying; Teng, Ningning; Li, Sen

    2016-09-01

    Tau fibrillation is reported to be involved in neurodegenerative disorders, such as Alzheimer's disease, in which the natural environment is very crowded in the cells. Understanding the role of crowding environments in regulating Tau fibrillation is of great importance for elucidating the etiology of these diseases. In this experiment, the effects of macromolecular crowding and osmolyte reagents in the crowding environment on Tau fibrillation were studied by thioflavin T binding, SDS-PAGE and TEM assays. Ficoll 70 and Dextran 70 of different concentrations were used as macromolecular crowding reagents inside the cells and showed a strong enhancing effect on the fibrillation of normal and hyperphosphorylated Tau. The enhancing effect of Dextran is stronger than that of Ficoll 70 at the same concentration. In addition, the cellular osmolyte sucrose was found to protect Tau against fibrillation, and inhibit the enhancing effect of macromolecular crowding on Tau fibrillation. A possible model for the fibrillation process of Tau and the effect of macromolecular crowding and osmolyte on this process was proposed based on these experimental results. The information obtained from our study can enhance the understanding of how proteins aggregate and avoid aggregation in crowded physiological environments and might lead to a better understanding of the molecular mechanisms of Alzheimer's disease in vivo.

  15. Measurement of the Tau- to F1(1285) Pi- Nu/Tau Branching Fraction And a Search for Second-Class Currents in Tau to Eta-Prime(958) Pi- Nu/Tau

    SciTech Connect

    Alwyn, K.E.; /Manchester U.

    2011-12-01

    The {tau}{sup -} {yields} {eta}{pi}{sup -}{pi}+{pi}{sup -}{nu}{tau} decay with the {eta} {yields} {gamma}{gamma} mode is studied using 384 fb{sup -1} of data collected by the BaBar detector. The branching fraction is measured to be (1.60 {+-} 0.05 {+-} 0.11) x 10{sup -4}. It is found that {tau}{sup -} {yields} f1(1285){pi}{sup -}{nu}{tau} {yields} {eta}{pi}{sup -}{pi}+{pi}{sup -}{nu}{tau} is the dominant decay mode with a branching fraction of (1.11 {+-} 0.06 {+-} 0.05) x 10{sup -4}. The first error is statistical and the second systematic. In addition, a 90% confidence level upper limit on the branching fraction of the {tau}{sup -} {yields} {eta}{prime}(958){pi}{sup -}{nu}{tau} decay is measured to be 7.2 x 10{sup -6}. This last decay proceeds through a second-class current and is expected to be forbidden in the limit of isospin symmetry.

  16. H4K5 histone acetylation of BRG1 is associated with heroin administration rather than addiction.

    PubMed

    Xu, Limin; Hong, Qingxiao; Chen, Xiaoying; Xu, Xuting; Liu, Huifen; Zhou, Wenhua; Duan, Shiwei

    2016-09-01

    Diacetylmorphine hydrochloride (heroin) addiction is a chronic relapsing brain disorder that is a heavy public health burden worldwide. Brm/SWI2-related gene-1 (BRG1) is a tumor suppressor gene that can influence embryogenesis and the development of the cerebellum. The current study aimed to investigate the effect of histone H4 lysine 5 (H4K5) modifications on the BRG1 gene in brain tissue of the ventral tegmental area (VTA) of heroin-addicted rats. A total of 21 male Sprague Dawley rats were raised in a standard manner and underwent heroin self-administration training. Rats were randomly divided into three equal groups: Group A, self-administered delivery of heroin; group B, yoked delivery of heroin; and group C, yoked delivery of saline. The VTA was harvested and subjected to chromatin immunoprecipitation (ChIP) analysis. Gene expression was evaluated by quantitative polymerase chain reaction. We calculated the recovery rate, which indicated the percentage of the total input BRG1 recovered by ChIP. Our results showed that BRG1 was less associated with H4K5 histone modification in the group of rats that underwent heroin self-administration than in the other two groups (A vs. B, P=0.031; A vs. C, P=0.067). The recovery fold changes of the self-administration group and the passive-administration group were significantly different from those of the group with yoked saline (A vs. C, P=0.013; B vs. C, P=0.009; A vs. B, P=0.731). The results of the current study demonstrated that H4K5 histone acetylation of BRG1 in the VTA may be associated with heroin administration, but not addiction.

  17. H4K5 histone acetylation of BRG1 is associated with heroin administration rather than addiction

    PubMed Central

    Xu, Limin; Hong, Qingxiao; Chen, Xiaoying; Xu, Xuting; Liu, Huifen; Zhou, Wenhua; Duan, Shiwei

    2016-01-01

    Diacetylmorphine hydrochloride (heroin) addiction is a chronic relapsing brain disorder that is a heavy public health burden worldwide. Brm/SWI2-related gene-1 (BRG1) is a tumor suppressor gene that can influence embryogenesis and the development of the cerebellum. The current study aimed to investigate the effect of histone H4 lysine 5 (H4K5) modifications on the BRG1 gene in brain tissue of the ventral tegmental area (VTA) of heroin-addicted rats. A total of 21 male Sprague Dawley rats were raised in a standard manner and underwent heroin self-administration training. Rats were randomly divided into three equal groups: Group A, self-administered delivery of heroin; group B, yoked delivery of heroin; and group C, yoked delivery of saline. The VTA was harvested and subjected to chromatin immunoprecipitation (ChIP) analysis. Gene expression was evaluated by quantitative polymerase chain reaction. We calculated the recovery rate, which indicated the percentage of the total input BRG1 recovered by ChIP. Our results showed that BRG1 was less associated with H4K5 histone modification in the group of rats that underwent heroin self-administration than in the other two groups (A vs. B, P=0.031; A vs. C, P=0.067). The recovery fold changes of the self-administration group and the passive-administration group were significantly different from those of the group with yoked saline (A vs. C, P=0.013; B vs. C, P=0.009; A vs. B, P=0.731). The results of the current study demonstrated that H4K5 histone acetylation of BRG1 in the VTA may be associated with heroin administration, but not addiction. PMID:27588112

  18. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy.

    PubMed

    Kovacs, Gabor G; Ferrer, Isidro; Grinberg, Lea T; Alafuzoff, Irina; Attems, Johannes; Budka, Herbert; Cairns, Nigel J; Crary, John F; Duyckaerts, Charles; Ghetti, Bernardino; Halliday, Glenda M; Ironside, James W; Love, Seth; Mackenzie, Ian R; Munoz, David G; Murray, Melissa E; Nelson, Peter T; Takahashi, Hitoshi; Trojanowski, John Q; Ansorge, Olaf; Arzberger, Thomas; Baborie, Atik; Beach, Thomas G; Bieniek, Kevin F; Bigio, Eileen H; Bodi, Istvan; Dugger, Brittany N; Feany, Mel; Gelpi, Ellen; Gentleman, Stephen M; Giaccone, Giorgio; Hatanpaa, Kimmo J; Heale, Richard; Hof, Patrick R; Hofer, Monika; Hortobágyi, Tibor; Jellinger, Kurt; Jicha, Gregory A; Ince, Paul; Kofler, Julia; Kövari, Enikö; Kril, Jillian J; Mann, David M; Matej, Radoslav; McKee, Ann C; McLean, Catriona; Milenkovic, Ivan; Montine, Thomas J; Murayama, Shigeo; Lee, Edward B; Rahimi, Jasmin; Rodriguez, Roberta D; Rozemüller, Annemieke; Schneider, Julie A; Schultz, Christian; Seeley, William; Seilhean, Danielle; Smith, Colin; Tagliavini, Fabrizio; Takao, Masaki; Thal, Dietmar Rudolf; Toledo, Jon B; Tolnay, Markus; Troncoso, Juan C; Vinters, Harry V; Weis, Serge; Wharton, Stephen B; White, Charles L; Wisniewski, Thomas; Woulfe, John M; Yamada, Masahito; Dickson, Dennis W

    2016-01-01

    Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of

  19. Mechanisms of Tau and Aβ-induced Excitotoxicity

    PubMed Central

    Pallo, Susanne P.; DiMaio, John; Cook, Alexis; Nilsson, Bradley; Johnson, Gail V.W.

    2016-01-01

    Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer’s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau−/−) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca2+ influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca2+ influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca2+ influx. While Aβ biphasically modulated the KA-induced Ca2+cyt responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca2+ influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 minutes) enhanced KA-induced Ca2+ influx, while chronic Aβ (24 hours) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca2+ influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1 mGluR activation. PMID:26731336

  20. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

    PubMed Central

    Ferrer, Isidro; Grinberg, Lea T.; Alafuzoff, Irina; Attems, Johannes; Budka, Herbert; Cairns, Nigel J.; Crary, John F.; Duyckaerts, Charles; Ghetti, Bernardino; Halliday, Glenda M.; Ironside, James W.; Love, Seth; Mackenzie, Ian R.; Munoz, David G.; Murray, Melissa E.; Nelson, Peter T.; Takahashi, Hitoshi; Trojanowski, John Q.; Ansorge, Olaf; Arzberger, Thomas; Baborie, Atik; Beach, Thomas G.; Bieniek, Kevin F.; Bigio, Eileen H.; Bodi, Istvan; Dugger, Brittany N.; Feany, Mel; Gelpi, Ellen; Gentleman, Stephen M.; Giaccone, Giorgio; Hatanpaa, Kimmo J.; Heale, Richard; Hof, Patrick R.; Hofer, Monika; Hortobágyi, Tibor; Jellinger, Kurt; Jicha, Gregory A.; Ince, Paul; Kofler, Julia; Kövari, Enikö; Kril, Jillian J.; Mann, David M.; Matej, Radoslav; McKee, Ann C.; McLean, Catriona; Milenkovic, Ivan; Montine, Thomas J.; Murayama, Shigeo; Lee, Edward B.; Rahimi, Jasmin; Rodriguez, Roberta D.; Rozemüller, Annemieke; Schneider, Julie A.; Schultz, Christian; Seeley, William; Seilhean, Danielle; Smith, Colin; Tagliavini, Fabrizio; Takao, Masaki; Thal, Dietmar Rudolf; Toledo, Jon B.; Tolnay, Markus; Troncoso, Juan C.; Vinters, Harry V.; Weis, Serge; Wharton, Stephen B.; White, Charles L.; Wisniewski, Thomas; Woulfe, John M.; Yamada, Masahito

    2016-01-01

    Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of

  1. Heavy-neutrino effects on tau-lepton decays

    NASA Astrophysics Data System (ADS)

    Pilaftsis, A.

    1994-11-01

    Minimal extensions of the Standard Model that are motivated by grand unified theories or superstring models with an E(6) symmetry can naturally predict heavy neutrinos of a Dirac or Majorana nature. Such heavy neutral leptons violate the decoupling theorem at the one-loop electroweak order and hence offer a unique chance for possible lepton-flavor decays of the tau lepton, e.g. tau to eee or tau to (mu)(mu)(mu), to be seen in LEP experiments. We analyze such decays in models with three and four generations.

  2. Search for lepton flavor violating decays tau+/--->l+/-omega.

    PubMed

    Aubert, B; Bona, M; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Grauges, E; Lopez, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes Pegna, D; Lynch, G; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabe, T; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Soni, N; Watson, A T; Koch, H; Schroeder, T; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Buzykaev, A R; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Echenard, B; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Ayad, R; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Nash, J A; Panduro Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Biesiada, J; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Roethel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; Nelson, S; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Wulsin, H W; Yarritu, A K; Yi, K; Young, C C; Ziegler, V; Burchat, P R; Edwards, A J; Majewski, S A; Miyashita, T S; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Pan, B; Saeed, M A; Zain, S B; Spanier, S M; Wogsland, B J; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2008-02-22

    A search for lepton flavor violating decays of a tau to a lighter-mass charged lepton and an omega vector meson is performed using 384.1 fb(-1) of e(+)e(-) annihilation data collected with the BABAR detector at the Stanford Linear Accelerator Center PEP-II storage ring. No signal is found, and the upper limits on the branching ratios are determined to be B(tau(+/-)-->e;{+/-}omega)<1.1 x10 (-7) and B(tau(+/-)-->micro(+/-)omega)<1.0 x 10(-7) at 90% confidence level.

  3. Presynaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease

    PubMed Central

    Sokolow, Sophie; Henkins, Kristen M.; Bilousova, Tina; Gonzalez, Bianca; Vinters, Harry V.; Miller, Carol A.; Cornwell, Lindsey; Poon, Wayne W.; Gylys, Karen H.

    2015-01-01

    The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from presynaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the presynaptic compartment in AD. PMID:25393609

  4. Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology?

    PubMed

    Belarbi, K; Burnouf, S; Fernandez-Gomez, F-J; Desmercières, J; Troquier, L; Brouillette, J; Tsambou, L; Grosjean, M-E; Caillierez, R; Demeyer, D; Hamdane, M; Schindowski, K; Blum, D; Buée, L

    2011-09-01

    Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.

  5. Chronic noise exposure causes persistence of tau hyperphosphorylation and formation of NFT tau in the rat hippocampus and prefrontal cortex.

    PubMed

    Cui, Bo; Zhu, Lixing; She, Xiaojun; Wu, Mingquan; Ma, Qiang; Wang, Tianhui; Zhang, Na; Xu, Chuanxiang; Chen, Xuewei; An, Gaihong; Liu, Hongtao

    2012-12-01

    The non-auditory effects of noise exposure on the central nervous system have been established both epidemiologically and experimentally. Chronic noise exposure (CNE) has been associated with tau hyperphosphorylation and Alzheimer's disease (AD)-like pathological changes. However, experimental evidence for these associations remains limited. The aim of the current study was to explore the effects of CNE [100 dB sound pressure level (SPL) white noise, 4 h/d×14 d] on tau phosphorylation in the rat hippocampus and the prefrontal cortex. Forty-eight male Wistar rats were randomly assigned to two groups: a noise-exposed group and a control group. The levels of radioimmunoprecipitation assay (RIPA)-soluble and RIPA-insoluble phosphorylated tau at Ser202, Ser396, Ser404, and Ser422 in the hippocampus and the prefrontal cortex were measured at different time points (days 0, 3, 7, and 14) after the end of the last noise exposure. Exposure to white noise for 14 consecutive days significantly increased the levels of tau phosphorylation at Ser202, Ser396, Ser404, and Ser422, the sites typically phosphorylated in AD brains, in the hippocampus and the prefrontal cortex. Tau hyperphosphorylation persisted for 7 to 14 d after the cessation of noise exposure. These alterations were also concomitant with the generation of pathological neurofibrillary tangle (NFT) tau 3, 7 and 14 d after the end of the stimulus. Furthermore, lasting increases in proteins involved in hyperphosphorylation, namely glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A), were found to occur in close correspondence with increase in tau hyperphosphorylation. The results of this study show that CNE leads to long-lasting increases in non-NFT hyperphosphorylated tau and delayed formation of misfolded NFT tau in the hippocampus and the prefrontal cortex. Our results also provide evidence for the involvement of GSK3β and PP2A in these processes.

  6. NAP alpha-aminoisobutyric acid (IsoNAP).

    PubMed

    Gozes, Illana; Schirer, Yulie; Idan-Feldman, Anat; David, Merav; Furman-Assaf, Sharon

    2014-01-01

    We set out to identify NAP (davunetide) analogs, providing neuroprotection and reducing tau pathology, specifically addressing protection against protein misfolding. NAP (NAPVSIPQ, intranasal formulation AL-108) is a drug candidate that (1) had a statistically significant impact on two measures, namely digit span and delayed-match-to-sample, tests of verbal recall and visual working memory, respectively, in patient population of mild cognitive impairment [preceding Alzheimer's disease (AD)] and (2) protected functional activities of daily living in schizophrenia patients. Previous preclinical studies have shown that stabilization of NAP by replacement of all L-amino acids by D-amino acids resulted in an active peptide, D-NAP. Other NAP mimetics are now explored. A new NAP analog was designed that included replacement of the proline residues by alpha-aminoisobutyric acid to enhance β-sheet breaker characteristics, thereby reducing protein misfolding. Three lines of investigations were chosen: (1) protection against the AD-associated amyloid β (1-42), Aβ1-42, peptide toxicity in cell cultures; (2) inhibition of AD-associated tau aggregation in vitro; and (3) cognitive protection in a mouse model of deficiencies of the NAP parent protein, activity-dependent neuroprotective protein (ADNP), exhibiting tau pathology and neurodegeneration. NAP alpha-aminoisobutyric acid (IsoNAP) protected neurons against AD-associated Aβ1-42-toxicity, inhibited the aggregation of the tau-derived peptide VQIVYK (important for the aggregation of tau into paired helical filaments, which form the tangles found in AD and related disorders), and protected cognitive functions in a model of ADNP deficiency. With AD being the major tauopathy, novel NAP derivatives that reduce tauopathy and provide neuroprotection as well as cognitive protection are of scientific and clinical interest.

  7. Study of High-multiplicity 3-prong and 5-prong Tau Decays at BaBar

    SciTech Connect

    Lees, J.P

    2012-06-01

    We present measurements of the branching fractions of 3-prong and 5-prong {tau} decay modes using a sample of 430 million {tau} lepton pairs, corresponding to an integrated luminosity of 468 fb{sup -1}, collected with the BABAR detector at the PEP-II asymmetric energy e{sup +}e{sup -} storage rings. The {tau}{sup -} {yields} (3{pi}){sup -} {eta}{nu}{sub {tau}}, {tau}{sup -} {yields} (3{pi}){sup -} {yields} {omega}{nu}{sub {tau}} and {tau}{sup -} {yields} {pi}{sup -} f{sub 1}(1285){nu}{sub {tau}} branching fractions are presented as well as a new limit on the branching fraction of the isospin-forbidden, second-class current {tau}{sup -} {yields} {pi}{sup -} {eta}{prime}(958){nu}{sub {tau}} decay. We find no evidence for charged kaons in these decay modes and place the first upper limits on their branching fractions.

  8. Lost after translation: missorting of Tau protein and consequences for Alzheimer disease.

    PubMed

    Zempel, Hans; Mandelkow, Eckhard

    2014-12-01

    Tau is a microtubule-associated-protein that is sorted into neuronal axons in physiological conditions. In Alzheimer disease (AD) and other tauopathies, Tau sorting mechanisms fail and Tau becomes missorted into the somatodendritic compartment. In AD, aberrant amyloid-β (Aβ) production might trigger Tau missorting. The physiological axonal sorting of Tau depends on the developmental stage of the neuron, the phosphorylation state of Tau and the microtubule cytoskeleton. Disease-associated missorting of Tau is connected to increased phosphorylation and aggregation of Tau, and impaired microtubule interactions. Disease-causing mechanisms involve impaired transport, aberrant kinase activation, non-physiological interactions of Tau, and prion-like spreading. In this review we focus on the physiological and pathological (mis)sorting of Tau, the underlying mechanisms, and effects in disease.

  9. Measurement of the absolute branching fraction of Ds+ --> tau+ nutau decay.

    PubMed

    Ecklund, K M; Love, W; Savinov, V; Lopez, A; Mendez, H; Ramirez, J; Ge, J Y; Miller, D H; Shipsey, I P J; Xin, B; Adams, G S; Anderson, M; Cummings, J P; Danko, I; Hu, D; Moziak, B; Napolitano, J; He, Q; Insler, J; Muramatsu, H; Park, C S; Thorndike, E H; Yang, F; Artuso, M; Blusk, S; Khalil, S; Li, J; Mountain, R; Nisar, S; Randrianarivony, K; Sultana, N; Skwarnicki, T; Stone, S; Wang, J C; Zhang, L M; Bonvicini, G; Cinabro, D; Dubrovin, M; Lincoln, A; Rademacker, J; Asner, D M; Edwards, K W; Naik, P; Reed, J; Briere, R A; Ferguson, T; Tatishvili, G; Vogel, H; Watkins, M E; Rosner, J L; Alexander, J P; Cassel, D G; Duboscq, J E; Ehrlich, R; Fields, L; Gibbons, L; Gray, R; Gray, S W; Hartill, D L; Heltsley, B K; Hertz, D; Jones, C D; Kandaswamy, J; Kreinick, D L; Kuznetsov, V E; Mahlke-Krüger, H; Mohapatra, D; Onyisi, P U E; Patterson, J R; Peterson, D; Riley, D; Ryd, A; Sadoff, A J; Shi, X; Stroiney, S; Sun, W M; Wilksen, T; Athar, S B; Patel, R; Yelton, J; Rubin, P; Eisenstein, B I; Karliner, I; Mehrabyan, S; Lowrey, N; Selen, M; White, E J; Wiss, J; Mitchell, R E; Shepherd, M R; Besson, D; Pedlar, T K; Cronin-Hennessy, D; Gao, K Y; Hietala, J; Kubota, Y; Klein, T; Lang, B W; Poling, R; Scott, A W; Zweber, P; Dobbs, S; Metreveli, Z; Seth, K K; Tomaradze, A; Libby, J; Powell, A; Wilkinson, G

    2008-04-25

    Using a sample of tagged D(s)(+) decays collected near the D(s)(*+/-)D(s)(-/+) peak production energy in e(+)e(-) collisions with the CLEO-c detector, we study the leptonic decay D(s)(+)-->tau(+)nu(tau) via the decay channel tau(+)-->e(+)nu(e)nu(tau). We measure B(D(s)(+)-->tau(+)nu(tau))=(6.17+/-0.71+/-0.34)%, where the first error is statistical and the second systematic. Combining this result with our measurements of D(s)(+)-->mu(+)nu(mu) and D(s)(+)-->tau(+)nu(tau) (via tau(+)-->pi(+)nu(tau)), we determine f(D(s))=(274+/-10+/-5) MeV.

  10. Search for CP Violation in the Decay tau- \\to pi- K^0_S (>= 0 pi0) nu_tau

    SciTech Connect

    Lees, J.P.; Poireau, V.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Milanes, D.A.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Brown, D.N.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; Koch, H.; Schroeder, T.; Asgeirsson, D.J.; Hearty, C.; Mattison, T.S.; McKenna, J.A.; /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /Indian Inst. Tech., Guwahati /Harvard U. /Harvey Mudd Coll. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa State U. /Iowa State U. /Johns Hopkins U. /Paris U., VI-VII /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT /McGill U. /INFN, Milan /Milan U. /INFN, Milan /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /INFN, Naples /Naples U. /NIKHEF, Amsterdam /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Padua /Padua U. /INFN, Padua /INFN, Padua /Padua U. /Paris U., VI-VII /INFN, Perugia /Perugia U. /INFN, Pisa /Pisa U. /Pisa U. /Pisa, Scuola Normale Superiore /INFN, Pisa /Pisa U. /INFN, Pisa /INFN, Pisa /Pisa U. /INFN, Pisa /Princeton U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /Rostock U. /Rutherford /DAPNIA, Saclay /SLAC /South Carolina U. /Southern Methodist U. /Stanford U., Phys. Dept. /SUNY, Albany /Tel Aviv U. /Tennessee U. /Texas Nuclear Corp., Austin /Texas U., Dallas /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /Valencia U. /Victoria U. /Warwick U. /Wisconsin U., Madison

    2012-02-16

    We report a search for CP violation in the decay {tau}{sup -} {yields} {pi}{sup -}K{sub S}{sup 0}({>=} 0{pi}{sup 0}){nu}{sub {tau}} using a dataset of 437 million {tau} lepton pairs, corresponding to an integrated luminosity of 476 fb{sup -1}, collected with the BABAR detector at the PEP-II asymmetric energy e{sup +}e{sup -} storage rings. The CP-violating decay-rate asymmetry is determined to be (-0.45 {+-} 0.24 {+-} 0.11)%, approximately three standard deviations from the Standard Model prediction of (0.33 {+-} 0.01)%.

  11. Is tau ready for admission to the prion club?

    PubMed Central

    Hall, Garth F.; Patuto, Brian A.

    2012-01-01

    Aggregation-prone proteins associated with neurodegenerative disease, such as α synuclein and β amyloid, now appear to share key prion-like features with mammalian prion protein, such as the ability to recruit normal proteins to aggregates and to translocate between neurons. These features may shed light on the genesis of stereotyped lesion development patterns in conditions such as Alzheimer disease and Lewy Body dementia. We discuss the qualifications of tau protein as a possible “prionoid” mediator of lesion spread based on recent characterizations of the secretion, uptake and transneuronal transfer of human tau isoforms in a variety of tauopathy models, and in human patients. In particular, we consider (1) the possibility that prionoid behavior of misprocessed tau in neurodegenerative disease may involve other aggregation-prone proteins, including PrP itself, and (2) whether “prionlike” tau lesion propagation might include mechanisms other than protein-protein templating. PMID:22561167

  12. Visually timed action: time-out for 'tau'?

    PubMed

    Tresilian

    1999-08-01

    Bringing about desirable collisions (making interceptions) and avoiding unwanted collisions are critically important sensorimotor skills, which appear to require us to estimate the time remaining before collision occurs (time-to-collision). Until recently the theoretical approach to understanding time-to-collision estimation has been dominated by the tau-hypothesis, which has its origins in J.J. Gibson's ecological approach to perception. The hypothesis proposes that a quantity (tau), present in the visual stimulus, provides the necessary time-to-collision information. Empirical results and formal analyses have now accumulated to demonstrate conclusively that the tau-hypothesis is false. This article describes an alternative approach that is based on recent data showing that the information used in judging time-to-collision is task- and situation-dependent, is of many different origins (of which tau is just one) and is influenced by the information-processing constraints of the nervous system.

  13. Measurement of spectral functions in {tau} decay to two pseudoscalars

    SciTech Connect

    Perera, L.P.

    1998-05-01

    We have measured the invariant mass spectra of the hadronic systems in the decays {tau}{sup {minus}}{r_arrow}{pi}{sup {minus}}{pi}{sup 0}{nu}{sub {tau}} and {tau}{sup {minus}}{r_arrow}K{sub S}{sup 0}{pi}{sup 0}{nu}{sub {tau}} using data from the CLEO-II detector operating at the CESR e{sup +}e{sup {minus}} collider. We measured the resonance parameters of the {rho}(770), {rho}(1450) and K{sup {asterisk}}(892) vector mesons and compared our {pi}{sup {minus}}{pi}{sup 0} results with e{sup +}e{sup {minus}}{r_arrow}{pi}{sup +}{pi}{sup {minus}} as a test of CVC. {copyright} {ital 1998 American Institute of Physics.}

  14. Measurement of spectral functions in {tau} decay to two pseudoscalars

    SciTech Connect

    Perera, L. P.

    1998-05-29

    We have measured the invariant mass spectra of the hadronic systems in the decays {tau}{sup -}{yields}{pi}{sup -}{pi}{sup 0}{nu}{sub {tau}} and {tau}{sup -}{yields}K{sub S}{sup 0}{pi}{sup 0}{nu}{sub {tau}} using data from the CLEO-II detector operating at the CESR e{sup +}e{sup -} collider. We measured the resonance parameters of the {rho}(770), {rho}(1450) and K*(892) vector mesons and compared our {pi}{sup -}{pi}{sup 0} results with e{sup +}e{sup -}{yields}{pi}{sup +}{pi}{sup -} as a test of CVC.

  15. Interferometric Evidence for Warm Dust in the DQ Tau System

    NASA Astrophysics Data System (ADS)

    Boden, Andrew F.; Sargent, A.; Akeson, R.; Carpenter, J.

    2007-12-01

    We report on near-IR interferometric observations of the double-lined pre-main sequence (PMS) binary system DQ Tau. With these observations and the previous spectroscopic orbit & analysis by Mathieu et al 1997 we have estimated a preliminary visual orbit of the DQ Tau system. DQ Tau exhibits a significant near-IR excess, so modeling our interferometric data requires the inclusion of near-IR light from an 'excess' source. Remarkably this excess source appears compact in our data, similar in physical scale to the binary itself, rather than a significantly larger circumbinary disk. This compact emission appears to support arguments by Mathieu et al 1997 and Carr et al 2001 that there is significant near-IR flux from warm gas and dust near the DQ Tau binary, and that dynamical clearing expected in a binary system has not been completely successful in dispersing this material.

  16. Tau as a Therapeutic Target for Alzheimer’s Disease

    PubMed Central

    Boutajangout, Allal; Sigurdsson, Einar M.; Krishnamurthy, Pavan K.

    2012-01-01

    Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer’s disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained. PMID:21679154

  17. Structure and mechanism of action of tau aggregation inhibitors

    PubMed Central

    Cisek, Katryna; Cooper, Grace L.; Huseby, Carol J.; Kuret, Jeff

    2015-01-01

    Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for maximizing on-target efficacy while minimizing off-target side effects. PMID:25387336

  18. Argonne Tau-charm factory collider design study

    SciTech Connect

    Teng, L.C.; Crosbie, E.A.; Norem, J.

    1995-12-01

    The design approach and design principles for a Tau-charm Factory at Argonne were studied. These studies led to a set of preliminary parameters and tentative component features as presented in this paper.

  19. Identification of dihydropyridines that reduce cellular tau levels.

    PubMed

    Evans, Christopher G; Jinwal, Umesh K; Makley, Leah N; Dickey, Chad A; Gestwicki, Jason E

    2011-01-07

    A series of dihydropyridines were identified that have an effect on the accumulation of tau, an important target in Alzheimer's disease. The dihydropyridine collection was expanded using the Hantzsch multicomponent reaction to develop preliminary structure-activity relationships.

  20. Identification of Dihydropyridines That Reduce Cellular Tau Levels

    PubMed Central

    Evans, Christopher G.; Jinwal, Umesh K.; Makley, Leah N.

    2011-01-01

    A series of dihydropyridines were identified that have an effect on the accumulation of tau, an important target in Alzheimer's disease. The dihydropyridine collection was expanded using the Hantzsch multicomponent reaction to develop preliminary structure-activity relationships. PMID:21082080

  1. Lepton Flavour Violation in Tau Decays at BaBar

    SciTech Connect

    Wilson, F.F.; /Rutherford

    2011-11-07

    Recent results from {tau} physics studies at BABAR are presented with an emphasis on Lepton Flavour Violation measurements. The results from the current generation of B-meson Factories are already beginning to constrain the parameter space of models that go beyond the Standard Model. By the end of their data-taking, the current generation of B-meson factories will have produced nearly 2 billion {tau} pair decays. The physics potential of this legacy has only just begun to be exploited.

  2. Physics of a high-luminosity Tau-Charm Factory

    SciTech Connect

    King, M.E.

    1992-10-01

    This paper highlights the physics capabilities of a Tau-Charm Factory; i.e., high luminosity ({approximately}10{sup 33}cm{sup {minus}2}s{sup {minus}1}) e{sup +}e{sup {minus}} collider operating in the center-of-mass energy range of 3-5 GeV, with a high-precision, general-purpose detector. Recent developments in {tau} and charm physics are emphasized.

  3. Measurement of the tau lepton polarisation at LEP2

    NASA Astrophysics Data System (ADS)

    Abdallah, J.; Abreu, P.; Adam, W.; Adzic, P.; Albrecht, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P. P.; Amaldi, U.; Amapane, N.; Amato, S.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, P.; Apel, W.-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, J. E.; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G. J.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.-H.; Begalli, M.; Behrmann, A.; Ben-Haim, E.; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, M.; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, M.; Bonesini, M.; Boonekamp, M.; Booth, P. S. L.; Borisov, G.; Botner, O.; Bouquet, B.; Bowcock, T. J. V.; Boyko, I.; Bracko, M.; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J. M.; Buschbeck, B.; Buschmann, P.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Castro, N.; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, P.; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, S. U.; Cieslik, K.; Collins, P.; Contri, R.; Cosme, G.; Cossutti, F.; Costa, M. J.; Crennell, D.; Cuevas, J.; D'Hondt, J.; da Silva, T.; da Silva, W.; Dedovich, D.; Ricca, G. Della; de Angelis, A.; de Boer, W.; de Clercq, C.; de Lotto, B.; de Maria, N.; de Min, A.; de Paula, L.; di Ciaccio, L.; di Simone, A.; Doroba, K.; Drees, J.; Eigen, G.; Ekelof, T.; Ellert, M.; Elsing, M.; Santo, M. C. Espirito; Fanourakis, G.; Fassouliotis, D.; Feindt, M.; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, M.; Garcia, C.; Gavillet, Ph.; Gazis, E.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Goncalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, K.; Hamilton, K.; Haug, S.; Hauler, F.; Hedberg, V.; Hennecke, M.; Herr, H.; Hoffman, J.; Holmgren, S.-O.; Holt, P. J.; Houlden, M. A.; Jackson, J. N.; Jarlskog, G.; Jarry, P.; Jeans, D.; Johansson, E. K.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, F.; Katsanevas, S.; Katsoufis, E.; Kernel, G.; Kersevan, B. P.; Kerzel, U.; King, B. T.; Kjaer, N. J.; Kluit, P.; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, J.; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J. H.; Lopez, J. M.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.-C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Nulty, R. Mc; Meroni, C.; Migliore, E.; Mitaroff, W.; Mjoernmark, U.; Moa, T.; Moch, M.; Moenig, K.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim, L.; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nicolaidou, R.; Nikolenko, M.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J. P.; Palka, H.; Papadopoulou, Th. D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, A.; Petrolini, A.; Piedra, J.; Pieri, L.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Poireau, V.; Pol, M. E.; Polok, G.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Rames, J.; Read, A.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, P.; Richard, F.; Ridky, J.; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Roudeau, P.; Rovelli, T.; Ruhlmann-Kleider, V.; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Sander, C.; Savoy-Navarro, A.; Schwickerath, U.; Sekulin, R.; Siebel, M.; Sisakian, A.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Tabarelli, T.; Tegenfeldt, F.; Timmermans, J.; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tome, B.; Tonazzo, A.; Tortosa, P.; Travnicek, P.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Turluer, M.-L.; Tyapkin, I. A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, G.; van Dam, P.; van Eldik, J.; van Remortel, N.; van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verdier, P.; Verzi, V.; Vilanova, D.; Vitale, L.; Vrba, V.; Wahlen, H.; Washbrook, A. J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zhuravlov, V.; Zimin, N. I.; Zintchenko, A.; Zupan, M.; Delphi Collaboration

    2008-01-01

    A first measurement of the average polarisation Pτ of tau leptons produced in e+e- annihilation at energies significantly above the Z resonance is presented. The polarisation is determined from the kinematic spectra of tau hadronic decays. The measured value Pτ = - 0.164 ± 0.125 is consistent with the Standard Model prediction for the mean LEP energy of 197 GeV.

  4. Measurement of the tau lepton polarisation at LEP2

    NASA Astrophysics Data System (ADS)

    DELPHI Collaboration; Abdallah, J.; Abreu, P.; Adam, W.; Adzic, P.; Albrecht, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P. P.; Amaldi, U.; Amapane, N.; Amato, S.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, P.; Apel, W.-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, J. E.; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G. J.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.-H.; Begalli, M.; Behrmann, A.; Ben-Haim, E.; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, M.; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, M.; Bonesini, M.; Boonekamp, M.; Booth, P. S. L.; Borisov, G.; Botner, O.; Bouquet, B.; Bowcock, T. J. V.; Boyko, I.; Bracko, M.; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J. M.; Buschbeck, B.; Buschmann, P.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Castro, N.; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, P.; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, S. U.; Cieslik, K.; Collins, P.; Contri, R.; Cosme, G.; Cossutti, F.; Costa, M. J.; Crennell, D.; Cuevas, J.; D'Hondt, J.; da Silva, T.; da Silva, W.; Dedovich, D.; Ricca, G. Della; de Angelis, A.; de Boer, W.; de Clercq, C.; de Lotto, B.; de Maria, N.; de Min, A.; de Paula, L.; di Ciaccio, L.; di Simone, A.; Doroba, K.; Drees, J.; Eigen, G.; Ekelof, T.; Ellert, M.; Elsing, M.; Santo, M. C. Espirito; Fanourakis, G.; Fassouliotis, D.; Feindt, M.; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, M.; Garcia, C.; Gavillet, Ph.; Gazis, E.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Goncalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, K.; Hamilton, K.; Haug, S.; Hauler, F.; Hedberg, V.; Hennecke, M.; Herr, H.; Hoffman, J.; Holmgren, S.-O.; Holt, P. J.; Houlden, M. A.; Jackson, J. N.; Jarlskog, G.; Jarry, P.; Jeans, D.; Johansson, E. K.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, F.; Katsanevas, S.; Katsoufis, E.; Kernel, G.; Kersevan, B. P.; Kerzel, U.; King, B. T.; Kjaer, N. J.; Kluit, P.; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, J.; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J. H.; Lopez, J. M.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.-C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Nulty, R. Mc; Meroni, C.; Migliore, E.; Mitaroff, W.; Mjoernmark, U.; Moa, T.; Moch, M.; Moenig, K.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim, L.; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nicolaidou, R.; Nikolenko, M.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J. P.; Palka, H.; Papadopoulou, Th. D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, A.; Petrolini, A.; Piedra, J.; Pieri, L.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Poireau, V.; Pol, M. E.; Polok, G.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Rames, J.; Read, A.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, P.; Richard, F.; Ridky, J.; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Roudeau, P.; Rovelli, T.; Ruhlmann-Kleider, V.; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Sander, C.; Savoy-Navarro, A.; Schwickerath, U.; Sekulin, R.; Siebel, M.; Sisakian, A.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Tabarelli, T.; Tegenfeldt, F.; Timmermans, J.; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tome, B.; Tonazzo, A.; Tortosa, P.; Travnicek, P.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Turluer, M.-L.; Tyapkin, I. A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, G.; van Dam, P.; van Eldik, J.; van Remortel, N.; van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verdier, P.; Verzi, V.; Vilanova, D.; Vitale, L.; Vrba, V.; Wahlen, H.; Washbrook, A. J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zhuravlov, V.; Zimin, N. I.; Zintchenko, A.; Zupan, M.

    2008-01-01

    A first measurement of the average polarisation P of tau leptons produced in e+e- annihilation at energies significantly above the Z resonance is presented. The polarisation is determined from the kinematic spectra of tau hadronic decays. The measured value P=-0.164±0.125 is consistent with the Standard Model prediction for the mean LEP energy of 197 GeV.

  5. Immunological memory to hyperphosphorylated tau in asymptomatic individuals.

    PubMed

    Pascual, Gabriel; Wadia, Jehangir S; Zhu, Xueyong; Keogh, Elissa; Kükrer, Başak; van Ameijde, Jeroen; Inganäs, Hanna; Siregar, Berdien; Perdok, Gerrard; Diefenbach, Otto; Nahar, Tariq; Sprengers, Imke; Koldijk, Martin H; der Linden, Els C Brinkman-van; Peferoen, Laura A; Zhang, Heng; Yu, Wenli; Li, Xinyi; Wagner, Michelle; Moreno, Veronica; Kim, Julie; Costa, Martha; West, Kiana; Fulton, Zara; Chammas, Lucy; Luckashenak, Nancy; Fletcher, Lauren; Holland, Trevin; Arnold, Carrie; Anthony Williamson, R; Hoozemans, Jeroen J; Apetri, Adrian; Bard, Frederique; Wilson, Ian A; Koudstaal, Wouter; Goudsmit, Jaap

    2017-05-01

    Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG(+) memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.

  6. Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0399 TITLE: Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy PRINCIPAL INVESTIGATOR: John F...Include area code) October 2015 Annual Report 30 Sep 2014 - 29 Sep 2015 Molecular & Genetic Investigation of Tau in Chronic Traumatic Encephalopathy John...encephalopathy (CTE), but the underlying molecular changes remain unclear. Here, biochemical and genetic studies that deepen our understanding of the

  7. Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model.

    PubMed

    Sydow, Astrid; Van der Jeugd, Ann; Zheng, Fang; Ahmed, Tariq; Balschun, Detlef; Petrova, Olga; Drexler, Dagmar; Zhou, Lepu; Rune, Gabriele; Mandelkow, Eckhard; D'Hooge, Rudi; Alzheimer, Christian; Mandelkow, Eva-Maria

    2011-11-01

    The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP-17 mutation ΔK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates.

  8. Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo

    PubMed Central

    Gorsky, Marianna Karina; Burnouf, Sylvie; Dols, Jacqueline; Mandelkow, Eckhard; Partridge, Linda

    2016-01-01

    Dysfunction and accumulation of the microtubule-associated human Tau (hTau) protein into intraneuronal aggregates is observed in many neurodegenerative disorders including Alzheimer’s disease (AD). Reversible lysine acetylation has recently emerged as a post-translational modification that may play an important role in the modulation of hTau pathology. Acetylated hTau species have been observed within hTau aggregates in human AD brains and multi-acetylation of hTau in vitro regulates its propensity to aggregate. However, whether lysine acetylation at position 280 (K280) modulates hTau-induced toxicity in vivo is unknown. We generated new Drosophila transgenic models of hTau pathology to evaluate the contribution of K280 acetylation to hTau toxicity, by analysing the respective toxicity of pseudo-acetylated (K280Q) and pseudo-de-acetylated (K280R) mutant forms of hTau. We observed that mis-expression of pseudo-acetylated K280Q-hTau in the adult fly nervous system potently exacerbated fly locomotion defects and photoreceptor neurodegeneration. In addition, modulation of K280 influenced total hTau levels and phosphorylation without changing hTau solubility. Altogether, our results indicate that pseudo-acetylation of the single K280 residue is sufficient to exacerbate hTau neurotoxicity in vivo, suggesting that acetylated K280-hTau species contribute to the pathological events leading to neurodegeneration in AD. PMID:26940749

  9. Tau proteins harboring neurodegeneration-linked mutations impair kinesin translocation in vitro.

    PubMed

    Yu, Dezhi; LaPointe, Nichole E; Guzman, Elmer; Pessino, Veronica; Wilson, Leslie; Feinstein, Stuart C; Valentine, Megan T

    2014-01-01

    We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro. We employed complementary in vitro motility assays using purified recombinant kinesin, purified recombinant tau, and purified bovine brain α:β tubulin to isolate interactions among these components without any contribution by cellular regulatory mechanisms. We found that kinesin translocates slower along MTs assembled by any of three independent tau mutants (4-repeat P301L tau, 4-repeat ΔN296 tau, and 4-repeat R406W tau) relative to its translocation rate along MTs assembled by normal, 4-repeat wild type (WT) tau. Moreover, the R406W mutation exhibited isoform specific effects; while kinesin translocation along 4-repeat R406W tau assembled MTs is slower than along MTs assembled by 4-repeat WT tau, the R406W mutation had no effect in the 3-repeat tau context. These data provide strong support for the notion that aberrant modulation of kinesin translocation is a component of tau-mediated neuronal cell death and dementia. Finally, we showed that assembling MTs with taxol before coating them with mutant tau obscured effects of the mutant tau that were readily apparent using more physiologically relevant MTs assembled with tau alone, raising important issues regarding the use of taxol as an experimental reagent and novel insights into therapeutic mechanisms of taxol action.

  10. Recent developments in tau-based therapeutics for neurodegenerative diseases.

    PubMed

    Medina, Miguel

    2011-01-01

    Neurodegenerative diseases constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of Alzheimer's disease (AD), the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists has demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. Drug development efforts for AD in the last two decades have primarily focused on targets defined by the amyloid cascade hypothesis, so far with disappointing results. In contrast, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some targets with significant potential in the field and which might be on the verge of providing new treatment paradigms within the coming years. Among those strategies, immunotherapy approaches will be mostly discussed. An update on 2010 patents regarding different aspects of tau-based therapeutic strategies is also provided.

  11. Potent inhibition of tau fibrillization with a multivalent ligand

    SciTech Connect

    Honson, Nicolette S.; Jensen, Jordan R.; Darby, Michael V.; Kuret, Jeff

    2007-11-09

    Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer's disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at {approx}80 nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.

  12. Tau Isoform Composition Influences Rate and Extent of Filament Formation*

    PubMed Central

    Zhong, Qi; Congdon, Erin E.; Nagaraja, Haikady N.; Kuret, Jeff

    2012-01-01

    The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease. PMID:22539343

  13. A note on using alpha and stratified alpha to estimate the reliability of a test composed of item parcels.

    PubMed

    Rae, Gordon

    2008-11-01

    Several authors have suggested that prior to conducting a confirmatory factor analysis it may be useful to group items into a smaller number of item 'parcels' or 'testlets'. The present paper mathematically shows that coefficient alpha based on these parcel scores will only exceed alpha based on the entire set of items if W, the ratio of the average covariance of items between parcels to the average covariance of items within parcels, is greater than unity. If W is less than unity, however, and errors of measurement are uncorrelated, then stratified alpha will be a better lower bound to the reliability of a measure than the other two coefficients. Stratified alpha are also equal to the true reliability of a test when items within parcels are essentially tau-equivalent if one assumes that errors of measurement are not correlated.

  14. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.

    PubMed

    Stancu, Ilie-Cosmin; Vasconcelos, Bruno; Ris, Laurence; Wang, Peng; Villers, Agnès; Peeraer, Eve; Buist, Arjan; Terwel, Dick; Baatsen, Peter; Oyelami, Tutu; Pierrot, Nathalie; Casteels, Cindy; Bormans, Guy; Kienlen-Campard, Pascal; Octave, Jean-Nöel; Moechars, Diederik; Dewachter, Ilse

    2015-06-01

    Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABA(A)R-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique

  15. Preliminary Measurement of B(tau- ---> K- pi0 nu/tau) Using the BaBar Detector

    SciTech Connect

    Salvatore, F.; Lyon, A.J.; /Manchester U.

    2005-07-08

    A preliminary measurement of the branching fraction {Beta}({tau}{sup -} {yields} K{sup -}{pi}{sup 0}{nu}{sub {tau}}) is made using 124.4 fb{sup -1} of e{sup +}e{sup -} collision data provided by the PEP-II accelerator, operating primarily at {radical}s = 10.58 GeV, and recorded using the BABAR detector. They measure: {Beta}({tau}{sup -} {yields} K{sup -} {pi}{sup 0}{nu}{sub {tau}}) = (0.438 {+-} 0.004(stat) {+-} 0.022(syst))%. This result is the world's most precise measurement of this branching fraction to date and is consistent with the world average.

  16. Enhanced tau neutrino appearance through invisible decay

    NASA Astrophysics Data System (ADS)

    Pagliaroli, Giulia; Di Marco, Natalia; Mannarelli, Massimo

    2016-06-01

    The decay of neutrino mass eigenstates leads to a change of the conversion and survival probability of neutrino flavor eigenstates. Exploiting the recent results released by the long-baseline OPERA experiment we perform the statistical investigation of the neutrino invisible decay hypothesis in the νμ→ντ appearance channel. We find that the neutrino decay provides an enhancement of the expected tau appearance signal with respect to the standard oscillation scenario for the long-baseline OPERA experiment. The increase of the νμ→ντ conversion probability by the decay of one of the mass eigenstates is due to a reduction of the "destructive interference" among the different massive neutrino components. Despite data showing a very mild preference for invisible decays with respect to the oscillations only hypothesis, we provide an upper limit for the neutrino decay lifetime in this channel of τ3/m3≳1.3 ×10-13 s /eV at the 90% confidence level.

  17. Tau phosphorylation in human, primate, and rat brain: evidence that a pool of tau is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro.

    PubMed

    Garver, T D; Harris, K A; Lehman, R A; Lee, V M; Trojanowski, J Q; Billingsley, M L

    1994-12-01

    The extent of tau phosphorylation is thought to regulate the binding of tau to microtubules: Highly phosphorylated tau does not bind to tubules, whereas dephosphorylated tau can bind to microtubules. It is interesting that the extent of tau phosphorylation in vivo has not been accurately determined. Tau was rapidly isolated from human temporal neocortex and hippocampus, rhesus monkey temporal neocortex, and rat temporal neocortex and hippocampus under conditions that minimized dephosphorylation. In brain slices, we observed that tau isolated under such conditions largely existed in several phosphorylated states, including a pool that was highly phosphorylated; this was determined using epitope-specific monoclonal and polyclonal antibodies. This highly phosphorylated tau was dephosphorylated during a 120-min time course in vitro, presumably as a result of neuronal phosphatase activity. The slow-mobility forms of tau were shifted to faster-mobility forms following in vitro incubation with alkaline phosphatase. Laser densitometry was used to estimate the percent of tau in slow-mobility, highly phosphorylated forms. Approximately 25% of immunoreactive tau was present as slow-mobility (66- and 68-kDa) forms of tau. The percentage of immunoreactive tau in faster-mobility pools (42-54 kDa) increased in proportion to the decrease in content of 66-68-kDa tau as a function of neuronal phosphatases or alkaline phosphatase treatment. These data suggest that the turnover of phosphorylated sites on tau is rapid and depends on neuronal phosphatases. Furthermore, tau is highly phosphorylated in normal-appearing human, primate, and rodent brain.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action.

    PubMed

    Feinstein, H Eric; Benbow, Sarah J; LaPointe, Nichole E; Patel, Nirav; Ramachandran, Srinivasan; Do, Thanh D; Gaylord, Michelle R; Huskey, Noelle E; Dressler, Nicolette; Korff, Megan; Quon, Brady; Cantrell, Kristi Lazar; Bowers, Michael T; Lal, Ratnesh; Feinstein, Stuart C

    2016-06-01

    Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal 'projection domains' aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly. Native gel analyses of full-length tau and deletion constructs demonstrate that the N-terminal region leads to multiple bands, consistent with oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment (tau(45-230) ) assembles into heptamers/octamers. Ferguson analyses of denaturing gels demonstrates that tau(45-230) can dimerize even in sodium dodecyl sulfate. Atomic force microscopy reveals multiple levels of oligomerization by both full-length tau and tau(45-230) . Finally, ion mobility-mass spectrometric analyses of tau(106-144) , a small peptide containing the core of the hypothesized dimerization region, also demonstrate oligomerization. Thus, multiple independent strategies demonstrate that the N-terminal region of tau can mediate higher order oligomerization, which may have important implications for both normal and pathological tau action. The microtubule-associated protein tau is essential for neuronal development and maintenance, but is also central to Alzheimer's and related dementias. Unfortunately, the molecular mechanisms underlying normal and pathological tau action remain poorly understood. Here, we demonstrate that tau can homo-oligomerize, providing novel mechanistic models for normal tau action (promoting microtubule growth and

  19. Tau Pathology Spread in PS19 Tau Transgenic Mice Following Locus Coeruleus (LC) Injections of Synthetic Tau Fibrils is Determined by the LC’s Afferent and Efferent Connections

    PubMed Central

    Iba, Michiyo; McBride, Jennifer D.; Guo, Jing L.; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.-Y.

    2015-01-01

    Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed [25] that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle bearing neurons gradually cleared tau pathology by 6–12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique

  20. Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease

    PubMed Central

    Lai, Robert Y. K.; Harrington, Charles R.; Wischik, Claude M.

    2016-01-01

    Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. PMID:27070645

  1. Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats.

    PubMed

    Wray, Selina; Saxton, Malcolm; Anderton, Brian H; Hanger, Diane P

    2008-06-01

    Tangles containing hyperphosphorylated aggregates of insoluble tau are a pathological hallmark of progressive supranuclear palsy (PSP). Several phosphorylation sites on tau in PSP have been identified using phospho-specific antibodies, but no sites have been determined by direct sequencing due to the difficulty in enriching insoluble tau from PSP brain. We describe a new method to enrich insoluble PSP-tau and report eight phosphorylation sites [Ser46, Thr181, Ser202, Thr217, Thr231, Ser235, Ser396/Ser400 (one site) and Thr403/Ser404 (one site)] identified by mass spectrometry. We also describe a 35 kDa C-terminal tau fragment (tau35), lacking the N-terminus of tau but containing four microtubule-binding repeats (4R), that is present only in neurodegenerative disorders in which 4R tau is over-represented. Tau35 was readily detectable in PSP, corticobasal degeneration and 4R forms of fronto-temporal dementia with parkinsonism linked to chromosome 17, but was absent from control, Alzheimer's disease and Pick's disease brain. Our findings suggest the aggregatory characteristics of PSP-tau differ from those of insoluble tau in Alzheimer's disease brain and this might be related to the presence of a C-terminal cleavage product of tau.

  2. A note on using stratified alpha to estimate the composite reliability of a test composed of interrelated nonhomogeneous items.

    PubMed

    Rae, Gordon

    2007-06-01

    The relationship between stratified alpha (alpha(s)) and the reliability of a test composed of interrelated nonhomogeneous items is examined. It is mathematically demonstrated that when there is congeneric equivalence within the strata or subtests, the difference between the coefficients is a function of the variances of the loadings within the strata. When the items within each stratum are essentially tau equivalent, these variances are 0, and alpha(s) and true reliability are equal, provided errors of measurement are uncorrelated. If errors of measurement are positively correlated and there is essential tau equivalence within strata, stratified alpha will overestimate reliability. These findings indicate that recent studies involving stratified alpha (A. Kamata, A. Turhan, & E. Darandari, 2003; H. G. Osburn, 2000) need to be interpreted with some degree of caution. Nevertheless, the hypothetical population data presented in this article suggest that under certain circumstances, stratified alpha can be considerably greater than alpha and closer to the true reliability. Because the former is easily computed, it is recommended that with stratified tests, practicing researchers should routinely calculate both alpha and stratified alpha coefficients.

  3. Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model.

    PubMed

    Fox, Leora M; William, Christopher M; Adamowicz, David H; Pitstick, Rose; Carlson, George A; Spires-Jones, Tara L; Hyman, Bradley T

    2011-07-01

    Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and although they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Using fluorescent in situ hybridization to detect Arc messenger RNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared with untreated transgenics, restoring enrichment-induced Arc messenger RNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, although tangles do not preclude neurons from responding in a functional circuit.

  4. Lepton Universality, |V(Us)| and Search for Second Class Current in Tau Decays

    SciTech Connect

    Banerjee, Swagato; /Victoria U.

    2011-11-10

    Several hundred million {tau} decays have been studied with the BABAR detector at the PEP-II e{sup +}e{sup -} collider at the SLAC National Accelerator Laboratory. Recent results on Charged Current Lepton Universality and two independent measurements of |V{sub us}| using {tau}{sup -} {yields} e{sup -}{bar {nu}}{sub e}{nu}{sub {tau}}, {mu}{sup -}{bar {nu}}{sub {mu}}{nu}{sub {tau}}, {pi}{sup -}{nu}{sub {tau}}, K{sup -} {nu}{sub {tau}} and K{sub S}{sup 0}{pi}{sup -} {nu}{sub {tau}} decays, and a search for Second Class Current in {tau}{sup -} {yields} {pi}{sup -} {omega}{nu}{sub {tau}} decays are presented, where the charge conjugate decay modes are also implied.

  5. Evidence for the Appearance of Atmospheric Tau Neutrinos in Super-Kamiokande

    NASA Astrophysics Data System (ADS)

    Abe, K.; Hayato, Y.; Iida, T.; Iyogi, K.; Kameda, J.; Koshio, Y.; Kozuma, Y.; Marti, Ll.; Miura, M.; Moriyama, S.; Nakahata, M.; Nakayama, S.; Obayashi, Y.; Sekiya, H.; Shiozawa, M.; Suzuki, Y.; Takeda, A.; Takenaga, Y.; Ueno, K.; Ueshima, K.; Yamada, S.; Yokozawa, T.; Ishihara, C.; Kaji, H.; Kajita, T.; Kaneyuki, K.; Lee, K. P.; McLachlan, T.; Okumura, K.; Shimizu, Y.; Tanimoto, N.; Labarga, L.; Kearns, E.; Litos, M.; Raaf, J. L.; Stone, J. L.; Sulak, L. R.; Goldhaber, M.; Bays, K.; Kropp, W. R.; Mine, S.; Regis, C.; Renshaw, A.; Smy, M. B.; Sobel, H. W.; Ganezer, K. S.; Hill, J.; Keig, W. E.; Jang, J. S.; Kim, J. Y.; Lim, I. T.; Albert, J. B.; Scholberg, K.; Walter, C. W.; Wendell, R.; Wongjirad, T. M.; Ishizuka, T.; Tasaka, S.; Learned, J. G.; Matsuno, S.; Smith, S. N.; Hasegawa, T.; Ishida, T.; Ishii, T.; Kobayashi, T.; Nakadaira, T.; Nakamura, K.; Nishikawa, K.; Oyama, Y.; Sakashita, K.; Sekiguchi, T.; Tsukamoto, T.; Suzuki, A. T.; Takeuchi, Y.; Ikeda, M.; Minamino, A.; Nakaya, T.; Fukuda, Y.; Itow, Y.; Mitsuka, G.; Tanaka, T.; Jung, C. K.; Lopez, G. D.; Taylor, I.; Yanagisawa, C.; Ishino, H.; Kibayashi, A.; Mino, S.; Mori, T.; Sakuda, M.; Toyota, H.; Kuno, Y.; Yoshida, M.; Kim, S. B.; Yang, B. S.; Okazawa, H.; Choi, Y.; Nishijima, K.; Koshiba, M.; Yokoyama, M.; Totsuka, Y.; Martens, K.; Schuemann, J.; Vagins, M. R.; Chen, S.; Heng, Y.; Yang, Z.; Zhang, H.; Kielczewska, D.; Mijakowski, P.; Connolly, K.; Dziomba, M.; Thrane, E.; Wilkes, R. J.

    2013-05-01

    Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42±0.35(stat)-0.12+0.14(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1±44.3(stat)-15.2+17.8(syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.

  6. Evidence for the appearance of atmospheric tau neutrinos in super-Kamiokande.

    PubMed

    Abe, K; Hayato, Y; Iida, T; Iyogi, K; Kameda, J; Koshio, Y; Kozuma, Y; Marti, Ll; Miura, M; Moriyama, S; Nakahata, M; Nakayama, S; Obayashi, Y; Sekiya, H; Shiozawa, M; Suzuki, Y; Takeda, A; Takenaga, Y; Ueno, K; Ueshima, K; Yamada, S; Yokozawa, T; Ishihara, C; Kaji, H; Kajita, T; Kaneyuki, K; Lee, K P; McLachlan, T; Okumura, K; Shimizu, Y; Tanimoto, N; Labarga, L; Kearns, E; Litos, M; Raaf, J L; Stone, J L; Sulak, L R; Goldhaber, M; Bays, K; Kropp, W R; Mine, S; Regis, C; Renshaw, A; Smy, M B; Sobel, H W; Ganezer, K S; Hill, J; Keig, W E; Jang, J S; Kim, J Y; Lim, I T; Albert, J B; Scholberg, K; Walter, C W; Wendell, R; Wongjirad, T M; Ishizuka, T; Tasaka, S; Learned, J G; Matsuno, S; Smith, S N; Hasegawa, T; Ishida, T; Ishii, T; Kobayashi, T; Nakadaira, T; Nakamura, K; Nishikawa, K; Oyama, Y; Sakashita, K; Sekiguchi, T; Tsukamoto, T; Suzuki, A T; Takeuchi, Y; Ikeda, M; Minamino, A; Nakaya, T; Fukuda, Y; Itow, Y; Mitsuka, G; Tanaka, T; Jung, C K; Lopez, G D; Taylor, I; Yanagisawa, C; Ishino, H; Kibayashi, A; Mino, S; Mori, T; Sakuda, M; Toyota, H; Kuno, Y; Yoshida, M; Kim, S B; Yang, B S; Okazawa, H; Choi, Y; Nishijima, K; Koshiba, M; Yokoyama, M; Totsuka, Y; Martens, K; Schuemann, J; Vagins, M R; Chen, S; Heng, Y; Yang, Z; Zhang, H; Kielczewska, D; Mijakowski, P; Connolly, K; Dziomba, M; Thrane, E; Wilkes, R J

    2013-05-03

    Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 ± 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.

  7. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development.

    PubMed

    Goedert, M; Jakes, R; Crowther, R A; Six, J; Lübke, U; Vandermeeren, M; Cras, P; Trojanowski, J Q; Lee, V M

    1993-06-01

    Tau is a neuronal phosphoprotein whose expression is developmentally regulated. A single tau isoform is expressed in fetal human brain but six isoforms are expressed in adult brain, with the fetal isoform corresponding to the shortest of the adult isoforms. Phosphorylation of tau is also developmentally regulated, as fetal tau is phosphorylated at more sites than adult tau. In Alzheimer disease, the six adult tau isoforms become abnormally phosphorylated and form the paired helical filament, the major fibrous component of the characteristic neurofibrillary lesions. We show here that Ser-202 (in the numbering of the longest human brain tau isoform) is a phosphorylation site that distinguishes fetal from adult tau and we identify it as one of the abnormal phosphorylation sites in Alzheimer disease. The abnormal phosphorylation of tau at Ser-202 in Alzheimer disease thus recapitulates normal phosphorylation during development.

  8. Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy.

    PubMed

    Kanaan, Nicholas M; Cox, Kristine; Alvarez, Victor E; Stein, Thor D; Poncil, Sharra; McKee, Ann C

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). Additionally, phosphorylation at serine 422 in tau occurs early and correlates with cognitive decline in patients with Alzheimer disease (AD). We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. Notably, the TauC3 epitope, which is abundant in AD, was relatively sparse in CTE. Together, these results provide the first description of PAD exposure, TOC1 reactive oligomers, phosphorylation of S422, and TauC3 truncation in the tau pathology of CTE.

  9. A search for the production of the final states. tau. sup +. tau. sup minus e sup + e sup minus ,. tau. sup +. tau. sup minus. mu. sup +. mu. sup minus , and. tau. sup +. tau. sup minus. pi. sup +. pi. sup minus in e sup + e sup minus collisions at radical s = 29 GeV

    SciTech Connect

    Not Available

    1991-07-01

    We have searched for the reaction e{sup +}e{sup {minus}} {yields} {tau}{sup +}{tau}{sup {minus}}{bar f}f, where f is either an electron, muon, or charged pion, at {radical}s = 29 GeV using the Mark 2 detector at the PEP storage ring. One candidate event is found while 2.3 events are expected from known processes. We would expect to see 11 events if the cross-section for e{sup +}e{sup {minus}} {yields} {tau}{sup +}{tau}{sup {minus}}{bar f}f at {radical}s = 29 GeV were enhanced by the factor of 4.7 which the ALEPH collaboration reports for {radical}s = 91 GeV. we also look for e{sup +}e{sup {minus}} {yields} e{sup +}e{sup {minus}}{bar f}f and e{sup +}e{sup {minus}} {yields} {mu}{sup +}{mu}{sup {minus}} {bar f}f, and for e{sup +}e{sup {minus}} {yields} {tau}{sup +}{tau}{sup {minus}} {gamma} using a similar analysis procedure and see the number of events predicted by the standard model. 10 refs., 5 figs., 3 tabs.

  10. Alpha storage regime in high temperature sub-ignited D-T tokamaks

    SciTech Connect

    Zweben, S.J.; Furth, H.P.; Mikkelsen, D.R.; Redi, M.H.; Strachan, J.D.

    1988-07-01

    Alpha particle parameters in sub-ignited D-T tokamaks like TFTR can be optimized in a high temperature ''alpha storage regime '' in which the alpha particle thermalization time /tau//sub ..cap alpha../ is long (approx.1.0 sec) and in which the alpha particle source rate S/sub ..cap alpha../ is enhanced due to a beam-target and beam-beam reactions (by a factor of approx.2-3). Near reactor-level alpha instability parameters ..beta../sub ..cap alpha../(0) approx. n/sub ..cap alpha../(0)/n/sub e/(O) approx. 1% are predicted by simulation codes when Q approx. 0.5-1, while present TFTR ''supershots'' already have ..beta../sub ..cap alpha../(O) approx. n/sub /alpha/(O)/n/sub e/(O) /approx/ 0.1-0.2%. Plasmas in this regime can be used to test theories of collective alpha instabilities for the first time, and can be used to provide a strong (but transient) alpha heating pulse. An experimental scenario to exploit this regime is described. 28 refs., 5 figs., 5 tabs.,

  11. Tau-positive nuclear indentations in P301S tauopathy mice.

    PubMed

    Fernández-Nogales, Marta; Santos-Galindo, María; Merchán-Rubira, Jesús; Hoozemans, Jeroen J M; Rábano, Alberto; Ferrer, Isidro; Avila, Jesús; Hernández, Félix; Lucas, José J

    2016-06-24

    Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term "tau nuclear rods (TNRs)." Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an

  12. ELISA measurement of specific antibodies to phosphorylated tau in intravenous immunoglobulin products.

    PubMed

    Loeffler, David A; Klaver, Andrea C; Coffey, Mary P

    2015-10-01

    The therapeutic effects of intravenous immunoglobulin (IVIG) products were recently studied in Alzheimer's disease (AD) patients. Pilot studies produced encouraging results but phase II and III trials gave disappointing results; a further study is in progress. IVIG products contain antibodies to tau protein, the main component of neurofibrillary tangles (NFTs). The tau used to detect IVIG's anti-tau antibodies in previous studies was non-phosphorylated recombinant human tau-441, but NFT-associated tau is extensively phosphorylated. The objective of this study was to determine if various IVIG products contain specific antibodies to phosphorylated tau (anti-pTau antibodies). ELISAs were used to evaluate binding of six IVIG products to a 12 amino acid peptide, tau 196-207, which was phosphorylated ("pTau peptide") or non-phosphorylated ("non-pTau peptide") at Serine-199 and Serine-202. Both amino acid residues are phosphorylated in AD NFTs. Each IVIG's "anti-pTau antibody ratio" was calculated by dividing its binding to the pTau peptide by its binding to the non-pTau peptide. Seven experiments were performed and data were pooled, with each experiment contributing one data point from each IVIG product. Mean anti-pTau antibody ratios greater than 1.0, suggesting specific antibodies to phosphorylated tau, were found for three IVIG products. Because administration of antibodies to phosphorylated tau has been found to reduce tau-associated pathology in transgenic mouse models of tauopathy, increasing the levels of anti-pTau antibodies, together with other selected antibodies such as anti-Aβ, in IVIG might increase its ability to slow AD's progression.

  13. Observations of AA Tau requested to schedule XMM-Newton

    NASA Astrophysics Data System (ADS)

    Waagen, Elizabeth O.

    2013-08-01

    Dr. Hans Moritz Guenther (Harvard-Smithsonian Center for Astrophysics) has requested nightly observations of the classical T Tauri star AA Tau in order to schedule x-ray observations with XMM-Newton that have been planned for between 2013 August 15 and September 15. The purpose of the AAVSO observations is to determine whether AA Tau is at a suitable magnitude for the satellite observations. Taurus is difficult to observe during this time period but that is exactly why AAVSO assistance is needed! AA Tau is a morning object, and also, many of the professional ground-based telescopes are offline because of the US southwest monsoon season. Since it is critical to know the brightness of AA Tau, AAVSO observations will be truly essential. Nightly visual and snapshot (not more than once per night) observations beginning now and continuing through September 20 are needed. Coverage beginning ahead of the XMM window is requested because there is a one- to two-week lead time for the target to be inserted into the telescope schedule. Continuing the nightly observations a few days beyond the end of the XMM window will give better optical context for the x-ray data. AA Tau ranges between ~12.8V and ~16.1V; since December 2011 or earlier it has been at ~14.5V. The most recent observation in the AAVSO International Database shows it at 14.779V on 2013 Feb 5 (J. Roe, Bourbon, MO). Dr. Guenther writes, "AA Tau is surrounded by a thick accretion disk which is seen nearly edge-on. For decades the light curve of AA Tau showed regular eclipsing events when the accretion funnel rotated through the line of sight. However, earlier this year J. Bouvier and his group found that this behavior changed dramatically: AA Tau now seems to be deeply absorbed all the time (V band 14.5 mag). In collaboration with this group we will perform X-ray observations of AA Tau with the XMM-Newton satellite." Finder charts with sequence may be created using the AAVSO Variable Star Plo! tter (http

  14. The Epstein-Barr Virus-encoded miR-BART22 targets MAP3K5 to promote host cell proliferative and invasive abilities in nasopharyngeal carcinoma

    PubMed Central

    Chen, Ruichao; Zhang, Minfeng; Li, Qiulian; Xiong, Hanzhen; Liu, Shaoyan; Fang, Weiyi; Zhang, Qianbing; Liu, Zhen; Xu, Xuehu; Jiang, Qingping

    2017-01-01

    miR-BART22, a new discovered Epstein-Barr virus (EBV) miRNA, is abundant in Nasopharyngeal carcinoma (NPC). It has been reported that miR-BART22 promoted the tumor development by down-modulating EBV LMP2 expression to evade the host immune response. But its cell target genes have still been obscure. We have reported an inverse correlation between the BART-22 and MAP3K5 protein expression in NPC tissues and NPC cell lines. Meanwhile, MAP3K5 protein expression level was significantly decreased in primary NPC tissues compared with nasopharyngitis when MAP3K5 mRNA expression was consistent in two group tissues. According to our data and target prediction by miRnada, we assume MAP3K5 is an important target gene of NPC. MAP3K5, also named apoptosis signal-regulating kinase1 (ASK1), is an important early answer gene in P38MAPK pathway and an apoptosis-related gene. In present study, MAP3K5 was verified the target gene of miR-BART22 by luciferase assay. miRBART-22 decreased MAP3K5 protein level. Moreover, it also decreased MAP3K5 downstream gene MAP2K4 expression in P38MAPK pathway, and even their activated phosphorylation forms. Additionally, we found stable transfection of miR-BAT22 could improve tumor cells' proliferative and invasive abilities in NPC cell line 5-8F. The data highlight the role of the EBV miR-BART22 in regulating genes involving in apoptosis and some important pathways to promote cancer development. And it also raises the possibility that inhibitors of miR-BART22 can be as a therapeutic strategy for NPC and other EBV-infected tumors treatment. PMID:28243335

  15. Oligomerization of the protein tau in the Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Larini, Luca

    The Alzheimer's disease is characterized by the formation of protein aggregates both within and outside of the brain's cells, the neurons. Within the neurons, the aggregation of the microtubule associated protein tau leads to the destruction of the microtubules in the axon of the neuron. Tau is extremely flexible and is classified as an intrinsically disordered protein due to its low propensity to form secondary structure. Tau promotes tubulin assembly into microtubules, which are an essential component of the cytoskeleton of the axon. The microtubule binding region of tau consists of 4 pseudo-repeats that are critical for aggregation as well. In this study, we focus on the aggregation propensity of different segments of the microtubule binding region as well as post-translational modifications that can alter tau dynamics and structure. We have performed replica exchange molecular dynamics simulations to characterize the ensemble of conformations of the monomer and small oligomers as well as how these structures are stabilized or destabilized by mutations and post-translational modifications.

  16. Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer's disease.

    PubMed

    Chalmers, Katy A; Wilcock, Gordon K; Vinters, Harry V; Perry, Elaine K; Perry, Robert; Ballard, Clive G; Love, Seth

    2009-05-01

    Cholinesterase inhibitors (ChEIs) are widely used for the symptomatic treatment of Alzheimer's disease (AD). In vitro and in animal studies, ChEIs have been shown to influence the processing of Abeta and the phosphorylation of tau, proteins that are the principal constituents of the plaques and neurofibrillary tangles, respectively, in AD brain. However, little is known about the effects of these drugs on Abeta and tau pathology in AD. Using avidin-biotin immunohistochemistry and computer-assisted image analysis, we compared Abeta and tau loads in the frontal and temporal cortices of 72 brains from matched cohorts of AD patients who had or had not received ChEIs. Patients treated with ChEIs had accumulated significantly more phospho-tau in their cerebral cortex than had untreated patients (P = 0.004). Abeta accumulation was reduced but not significantly. These data raise the possibility that increased tau phosphorylation may influence long-term clinical responsiveness to ChEIs.

  17. Multiple-motor based transport and its regulation by Tau

    PubMed Central

    Vershinin, Michael; Carter, Brian C.; Razafsky, David S.; King, Stephen J.; Gross, Steven P.

    2007-01-01

    Motor-based intracellular transport and its regulation are crucial to the functioning of a cell. Disruption of transport is linked to Alzheimer's and other neurodegenerative diseases. However, many fundamental aspects of transport are poorly understood. An important issue is how cells achieve and regulate efficient long-distance transport. Mounting evidence suggests that many in vivo cargoes are transported along microtubules by more than one motor, but we do not know how multiple motors work together or can be regulated. Here we first show that multiple kinesin motors, working in conjunction, can achieve very long distance transport and apply significantly larger forces without the need of additional factors. We then demonstrate in vitro that the important microtubule-associated protein, tau, regulates the number of engaged kinesin motors per cargo via its local concentration on microtubules. This function of tau provides a previously unappreciated mechanism to regulate transport. By reducing motor reattachment rates, tau affects cargo travel distance, motive force, and cargo dispersal. We also show that different isoforms of tau, at concentrations similar to those in cells, have dramatically different potency. These results provide a well defined mechanism for how altered tau isoform levels could impair transport and thereby lead to neurodegeneration without the need of any other pathway. PMID:17190808

  18. Oligomer Formation of Tau Protein Hyperphosphorylated in Cells*

    PubMed Central

    Tepper, Katharina; Biernat, Jacek; Kumar, Satish; Wegmann, Susanne; Timm, Thomas; Hübschmann, Sabrina; Redecke, Lars; Mandelkow, Eva-Maria; Müller, Daniel J.; Mandelkow, Eckhard

    2014-01-01

    Abnormal phosphorylation (“hyperphosphorylation”) and aggregation of Tau protein are hallmarks of Alzheimer disease and other tauopathies, but their causative connection is still a matter of debate. Tau with Alzheimer-like phosphorylation is also present in hibernating animals, mitosis, or during embryonic development, without leading to pathophysiology or neurodegeneration. Thus, the role of phosphorylation and the distinction between physiological and pathological phosphorylation needs to be further refined. So far, the systematic investigation of highly phosphorylated Tau was difficult because a reliable method of preparing reproducible quantities was not available. Here, we generated full-length Tau (2N4R) in Sf9 cells in a well defined phosphorylation state containing up to ∼20 phosphates as judged by mass spectrometry and Western blotting with phospho-specific antibodies. Despite the high concentration in living Sf9 cells (estimated ∼230 μm) and high phosphorylation, the protein was not aggregated. However, after purification, the highly phosphorylated protein readily formed oligomers, whereas fibrils were observed only rarely. Exposure of mature primary neuronal cultures to oligomeric phospho-Tau caused reduction of spine density on dendrites but did not change the overall cell viability. PMID:25339173

  19. High-fat, high-sugar, and high-cholesterol consumption does not impact tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology.

    PubMed

    Gratuze, Maud; Julien, Jacinthe; Morin, Françoise; Calon, Frédéric; Hébert, Sébastien S; Marette, André; Planel, Emmanuel

    2016-11-01

    Aggregates of hyperphosphorylated tau protein are a pathological hallmark of Alzheimer's disease (AD). The origin of AD is multifactorial, and many metabolic disorders originating from overconsumption of fat, cholesterol, and sugar are associated with higher risk of AD later in life. However, the effects of fat, cholesterol, and sugar overconsumption on tau pathology in AD remain controversial. Using the hTau mice, a model of AD-like tau pathology, we assessed the effects of high-fat, high-cholesterol, and/or high-sugar diets on tau pathogenesis. Surprisingly, we found no effects of these compounds, even combined, on tau phosphorylation, O-GlcNAcylation, splicing, cleavage, and aggregation, suggesting that their overconsumption does not seem to worsen tau pathology in these mice.

  20. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies.

    PubMed

    Dai, Chun-ling; Chen, Xia; Kazim, Syed Faraz; Liu, Fei; Gong, Cheng-Xin; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-04-01

    Intraneuronal accumulation of abnormally hyperphosphorylated tau in the brain is a histopathological hallmark of Alzheimer's disease and a family of related neurodegenerative disorders collectively called tauopathies. At present there is no effective treatment available for these progressive neurodegenerative diseases which are clinically characterized by dementia in mid to old-age. Here we report the treatment of 14-17-months-old 3xTg-AD mice with tau antibodies 43D (tau 6-18) and 77E9 (tau 184-195) to the N-terminal projection domain of tau or mouse IgG as a control by intraperitoneal injection once a week for 4 weeks, and the effects of the passive immunization on reduction of hyperphosphorylated tau, Aβ accumulation and cognitive performance in these animals. We found that treatment with tau antibodies 43D and 77E9 reduced total tau level, decreased tau hyperphosphorylated at Ser199, Ser202/Thr205 (AT8), Thr205, Ser262/356 (12E8), and Ser396/404 (PHF-1) sites, and a trend to reduce Aβ pathology. Most importantly, targeting N-terminal tau especially by 43D (tau 6-18) improved reference memory in the Morris water maze task in 3xTg-AD mice. We did not observe any abnormality in general physical characteristics of the treated animals with either of the two antibodies during the course of this study. Taken together, our studies demonstrate for the first time (1) that passive immunization targeting normal tau can effectively clear the hyperphosphorylated protein and possibly reduce Aβ pathology from the brain and (2) that targeting N-terminal projection domain of tau containing amino acid 6-18 is especially beneficial. Thus, targeting selective epitopes of N-terminal domain of tau may present a novel effective therapeutic opportunity for Alzheimer disease and other tauopathies.

  1. Measurement of the branching fraction for $\\tau\\to\\eta K\

    SciTech Connect

    del Amo Sanchez, P.; Lees, J.P.; Poireau, V.; Prencipe, E.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Battaglia, M.; Brown, D.N.; Hooberman, B.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; Osipenkov, I.L.; Tanabe, T.; /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /Indian Inst. Tech., Guwahati /Harvard U. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa State U. /Iowa State U. /Johns Hopkins U. /Paris U., VI-VII /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT /McGill U. /INFN, Milan /Milan U. /INFN, Milan /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /INFN, Naples /Naples U. /NIKHEF, Amsterdam /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Padua /Padua U. /INFN, Padua /INFN, Padua /Padua U. /Paris U., VI-VII /INFN, Perugia /Perugia U. /INFN, Pisa /Pisa U. /INFN, Pisa /Pisa, Scuola Normale Superiore /INFN, Pisa /Pisa U. /INFN, Pisa /Princeton U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /Rostock U. /Rutherford /DAPNIA, Saclay /SLAC /South Carolina U. /Southern Methodist U. /Stanford U., Phys. Dept. /SUNY, Albany /Tel Aviv U. /Tennessee U. /Texas U. /Texas U., Dallas /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /Valencia U. /Victoria U. /Warwick U. /Wisconsin U., Madison

    2011-08-12

    The authors report on analyses of tau lepton decays {tau}{sup -} {yields} {eta}K{sup -}{nu}{sub {tau}} and {tau}{sup -} {yields} {eta}{pi}{sup -}{nu}{sub {tau}}, with {eta} {yields} {pi}{sup +}{pi}{sup -}{pi}{sup 0}, using 470 fb{sup -1} of data from the BABAR experiment at PEP-II, collected at center-of-mass energies at and near the {Upsilon}(4S) resonance. They measure the branching fraction for the {tau}{sup -} {yields} {eta}K{sup -}{nu}{sub {tau}} decay mode, {Beta}({tau}{sup -} {yields} {eta}K{sup -}{nu}{sub {tau}}) = (1.42 {+-} 0.11(stat) {+-} 0.07(syst)) x 10{sup -4}, and report a 95% confidence level upper limit for the second-class current process {tau}{sup -} {yields} {eta}{pi}{sup -}{nu}{sub {tau}}, {Beta}({tau}{sup -} {yields} {eta}{pi}{sup -}{nu}{sub {tau}}) < 9.9 x 10{sup -5}.

  2. Search for Tau-Lepton Decays to Seven Or More Pions With BaBar

    SciTech Connect

    Kass, R.; Ter-Antonian, R.; Hast, C.; /SLAC

    2007-11-02

    We report the results of searches for several decay modes of the {tau}-lepton with {ge} 7 pions in the final state using 207 x 10{sup 6} {tau}-pairs collected with the BaBar detector. For the decays with 7 charged pions in the final state we find the following 90% CL upper limits: B({tau}{sup -} {yields} 4{pi}{sup -}3{pi}{sup +}({pi}{sup 0}){nu}{sub {tau}}) < 3.0 x 10{sup -7}, B({tau}{sup -} {yields} 4{pi}{sup -}3{pi}{sup +}{nu}{sub {tau}}) < 4.3 x 10{sup -7} and B({tau}{sup -} {yields}) B({tau}{sup -} {yields} 4{pi}{sup -}3{pi}{sup +}{pi}{sup 0}{nu}{sub {tau}}) < 2.5 x 10{sup -7}. We also search for the decay {tau}{sup -} {yields} 3{pi}{sup -}2{pi}{sup +}2{pi}{sup 0}{nu}{sub {tau}} and report a 90% CL upper limit of < 3.4 x 10{sup -6} for its branching fraction. Finally, we search for the exclusive final state {tau}{sup -} {yields} 2{sigma}{pi}{sup -}{nu}{sub {tau}} and find a 90% CL upper limit for its branching fraction of < 5.4 x 10{sup -7}.

  3. Monitoring of Intracellular Tau Aggregation Regulated by OGA/OGT Inhibitors.

    PubMed

    Lim, Sungsu; Haque, Md Mamunul; Nam, Ghilsoo; Ryoo, Nayeon; Rhim, Hyewhon; Kim, Yun Kyung

    2015-08-26

    Abnormal phosphorylation of tau has been considered as a key pathogenic mechanism inducing tau aggregation in multiple neurodegenerative disorders, collectively called tauopathies. Recent evidence showed that tau phosphorylation sites are protected with O-linked β-N-acetylglucosamine (O-GlcNAc) in normal brain. In pathological condition, tau is de-glycosylated and becomes a substrate for kinases. Despite the importance of O-GlcNAcylation in tau pathology, O-GlcNAc transferase (OGT), and an enzyme catalyzing O-GlcNAc to tau, has not been carefully investigated in the context of tau aggregation. Here, we investigated intracellular tau aggregation regulated by BZX2, an inhibitor of OGT. Upon the inhibition of OGT, tau phosphorylation increased 2.0-fold at Ser199 and 1.5-fold at Ser396, resulting in increased tau aggregation. Moreover, the BZX2 induced tau aggregation was efficiently reduced by the treatment of Thiamet G, an inhibitor of O-GlcNAcase (OGA). Our results demonstrated the protective role of OGT in tau aggregation and also suggest the counter-regulatory mechanism of OGA and OGT in tau pathology.

  4. Changes in microtubule-associated protein tau during peripheral nerve injury and regeneration

    PubMed Central

    Zha, Guang-bin; Shen, Mi; Gu, Xiao-song; Yi, Sheng

    2016-01-01

    Tau, a primary component of microtubule-associated protein, promotes microtubule assembly and/or disassembly and maintains the stability of the microtubule structure. Although the importance of tau in neurodegenerative diseases has been well demonstrated, whether tau is involved in peripheral nerve regeneration remains unknown. In the current study, we obtained sciatic nerve tissue from adult rats 0, 1, 4, 7, and 14 days after sciatic nerve crush and examined tau mRNA and protein expression levels and the location of tau in the sciatic nerve following peripheral nerve injury. The results from our quantitative reverse transcription polymerase chain reaction analysis showed that compared with the uninjured control sciatic nerve, mRNA expression levels for both tau and tau tubulin kinase 1, a serine/threonine kinase that regulates tau phosphorylation, were decreased following peripheral nerve injury. Our western blot assay results suggested that the protein expression levels of tau and phosphorylated tau initially decreased 1 day post nerve injury but then gradually increased. The results of our immunohistochemical labeling showed that the location of tau protein was not altered by nerve injury. Thus, these results showed that the expression of tau was changed following sciatic nerve crush, suggesting that tau may be involved in peripheral nerve repair and regeneration. PMID:27857758

  5. BAG3 facilitates the clearance of endogenous tau in primary neurons.

    PubMed

    Lei, Zhinian; Brizzee, Corey; Johnson, Gail V W

    2015-01-01

    Tau is a microtubule associated protein that is found primarily in neurons, and in pathologic conditions, such as Alzheimer's disease (AD) it accumulates and contributes to the disease process. Because tau plays a fundamental role in the pathogenesis of AD and other tauopathies, and in AD mouse models reducing tau levels improves outcomes, approaches that facilitate tau clearance are being considered as therapeutic strategies. However, fundamental to the development of such interventions is a clearer understanding of the mechanisms that regulate tau clearance. Here, we report a novel mechanism of tau degradation mediated by the co-chaperone BAG3. BAG3 has been shown to be an essential component of a complex that targets substrates to the autophagy pathway for degradation. In rat primary neurons, activation of autophagy by inhibition of proteasome activity or treatment with trehalose resulted in significant decreases in tau and phospho-tau levels. These treatments also induced an upregulation of BAG3. Proteasome inhibition activated JNK, which was responsible for the upregulation of BAG3 and increased tau clearance. Inhibiting JNK or knocking down BAG3 blocked the proteasome inhibition-induced decreases in tau. Further, BAG3 overexpression alone resulted in significant decreases in tau and phospho-tau levels in neurons. These results indicate that BAG3 plays a critical role in regulating the levels of tau in neurons, and interventions that increase BAG3 levels could provide a therapeutic approach in the treatment of AD.

  6. Development of tau aggregation inhibitors for Alzheimer's disease.

    PubMed

    Bulic, Bruno; Pickhardt, Marcus; Schmidt, Boris; Mandelkow, Eva-Maria; Waldmann, Herbert; Mandelkow, Eckhard

    2009-01-01

    A variety of human diseases are suspected to be directly linked to protein misfolding. Highly organized protein aggregates, called amyloid fibrils, and aggregation intermediates are observed; these are considered to be mediators of cellular toxicity and thus attract a great deal of attention from investigators. Neurodegenerative pathologies such as Alzheimer's disease account for a major part of these protein misfolding diseases. The last decade has witnessed a renaissance of interest in inhibitors of tau aggregation as potential disease-modifying drugs for Alzheimer's disease and other "tauopathies". The recent report of a phase II clinical trial with the tau aggregation inhibitor MTC could hold promise for the validation of the concept. This Review summarizes the available data concerning small-molecule inhibitors of tau aggregation from a medicinal chemistry point of view.

  7. Search for Lepton Flavor Violating Decays Tau+- to L+- Omega

    SciTech Connect

    Schenk, S.; /Heidelberg U.

    2011-11-30

    This paper reports on a search for lepton flavor violating decays of a {tau} lepton to a lighter-mass charged lepton and an {omega} vector meson. The data sample corresponds to an integrated luminosity of 384 fb{sup -1} recorded by the BaBar experiment at the SLAC PEP-II asymmetric-energy B Factory. No evidence for a signal is found and the upper limits on the branching ratios are determined to be B({tau}{sup {+-}} {yields} e{sup {+-}}{omega}) < 1.1 x 10{sup -7} and B({tau}{sup {+-}} {yields} {mu}{sup {+-}}{omega}) < 1.0 x 10{sup -7} at 90% confidence level.

  8. Rescue of tau-induced synaptic transmission pathology by paclitaxel

    PubMed Central

    Erez, Hadas; Shemesh, Or A.; Spira, Micha E.

    2014-01-01

    Behavioral and electrophysiological studies of Alzheimer’s disease (AD) and other tauopathies have revealed that the onset of cognitive decline correlates better with synaptic dysfunctions than with hallmark pathologies such as extracellular amyloid-β plaques, intracellular hyperphosphorylated tau or neuronal loss. Recent experiments have also demonstrated that anti-cancer microtubule (MT)-stabilizing drugs can rescue tau-induced behavioral decline and hallmark neuron pathologies. Nevertheless, the mechanisms underlying tau-induced synaptic dysfunction as well as those involved in the rescue of cognitive decline by MTs-stabilizing drugs remain unclear. Here we began to study these mechanisms using the glutaminergic sensory-motoneuron synapse derived from Aplysia ganglia, electrophysiological methods, the expression of mutant-human tau (mt-htau) either pre or postsynaptically and the antimitotic drug paclitaxel. Expression of mt-htau in the presynaptic neurons led to reduced excitatory postsynaptic potential (EPSP) amplitude generated by rested synapses within 3 days of mt-htau expression, and to deeper levels of homosynaptic depression. mt-htau-induced synaptic weakening correlated with reduced releasable presynaptic vesicle pools as revealed by the induction of asynchronous neurotransmitter release by hypertonic sucrose solution. Paclitaxel totally rescued tau-induced synaptic weakening by maintaining the availability of the presynaptic vesicle stores. Postsynaptic expression of mt-htau did not impair the above described synaptic-transmission parameters for up to 5 days. Along with earlier confocal microscope observations from our laboratory, these findings suggest that tau-induced synaptic dysfunction is the outcome of impaired axoplasmic transport and the ensuing reduction in the releasable presynaptic vesicle stores rather than the direct effects of mt-htau or paclitaxel on the synaptic release mechanisms. PMID:24574970

  9. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy

    PubMed Central

    Armstrong, Richard A.; McKee, Ann C.; Alvarez, Victor E.; Cairns, Nigel J.

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer’s disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease. PMID:27770214

  10. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy.

    PubMed

    Armstrong, Richard A; McKee, Ann C; Alvarez, Victor E; Cairns, Nigel J

    2017-02-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease.

  11. Nondeletional alpha-thalassemia: first description of alpha Hph alpha and alpha Nco alpha mutations in a Spanish population.

    PubMed

    Ayala, S; Colomer, D; Aymerich, M; Pujades, A; Vives-Corrons, J L

    1996-07-01

    Several different deletions underlie the molecular basis of alpha-thalassemia. The most common alpha-thalassemia determinant in Spain is the rightward deletion (-alpha 3.7). To our knowledge, however, no cases of alpha-thalassemia due to nondeletional mutations have so far been described in this particular Mediterranean area. Here, we report the existence of nondeletional forms of alpha-thalassemia in ten Spanish families. The alpha 2-globin gene was characterized in ten unrelated patients and their relatives only when the presence of deletional alpha-thalassemia was ruled out. The alpha 2-globin gene analysis was performed using the polymerase chain reaction (PCR) followed by restriction enzyme analysis or by allelespecific priming. This allowed the identification of a 5-base pair (bp) deletion at the donor site of IVS I (alpha Hph alpha) in 9 cases and the alpha 2 initiation codon mutation (alpha Nco alpha) in one case. Although these alpha 2-globin gene mutations are found in other mediterranean areas, our results demonstrate their presence in the Spanish population and suggest that the alpha Hph alpha/alpha alpha genotype is probably the most common nondeletional form of alpha-thalassemia in Spain.

  12. The strong coupling from tau decays without prejudice

    NASA Astrophysics Data System (ADS)

    Boito, Diogo; Golterman, Maarten; Jamin, Matthias; Mahdavi, Andisheh; Maltman, Kim; Osborne, James; Peris, Santiago

    2014-08-01

    We review our recent determination of the strong coupling αs from the OPAL data for non-strange hadronic tau decays. We find that αs (mτ2)= 0.325 ± 0.018 using fixed-order perturbation theory, and αs (mτ2)= 0.347 ± 0.025 using contour-improved perturbation theory. At present, these values supersede any earlier determinations of the strong coupling from hadronic tau decays, including those from ALEPH data.

  13. Atmospheric neutrino oscillations and tau neutrinos in ice

    SciTech Connect

    Giordano, Gerardo; Mocioiu, Irina; Mena, Olga

    2010-06-01

    The main goal of the IceCube Deep Core Array is to search for neutrinos of astrophysical origins. Atmospheric neutrinos are commonly considered as a background for these searches. We show here that cascade measurements in the Ice Cube Deep Core Array can provide strong evidence for tau neutrino appearance in atmospheric neutrino oscillations. Controlling systematic uncertainties will be the limiting factor in the analysis. A careful study of these tau neutrinos is crucial, since they constitute an irreducible background for astrophysical neutrino detection.

  14. Studies of the Strange Hadronic Tau Decay Tau- to K0(S) Pi- Nu-Tau Using the BaBar Detector

    SciTech Connect

    Lyon, Andrew J.; /Manchester U. /SLAC

    2006-01-27

    A study of the decay {tau}{sup -} {yields} K{sub S}{sup 0}{pi}{sup -} {nu}{sub {tau}} (K{sub S}{sup 0} {yields} {pi}{sup +}{pi}{sup -}) using the BABAR detector is presented. Using 124.4 fb{sup -1} of data we measure {Beta}({tau}{sup -} {yields} {bar K}{sup 0}{pi}{sup -}{nu}{sub {tau}}) = (0.830 {+-} 0.005(stat) {+-} 0.042(syst))%, which is the world's most precise measurement to date of this branching ratio, and is consistent with the current world average. This preliminary result, unlike most of the {Beta}({tau}{sup -} {yields} {bar K}{sup 0}{pi}{sup -}{nu}{sub {tau}}) measurements already published, is systematics dominated and so the biggest future improvement to this number should come from reducing the systematic uncertainties in the analysis. A study of the K{pi} mass spectrum, from which the strange (K{pi}) spectral function can be measured, reveals excess contributions above the K*(892) tail at higher K{pi} mass. While in the past this has been thought to be due to K*(892) - K*(1410) interference, we find that the K*(1410), whose branching ratio to K{pi} is approximately 7%, seems insufficient to explain the excess mass observed in the data. Instead, we perform a fit using a K*(892) - K*(1680) interference model and find better agreement. The discrepancy that remains could be due to an s-wave contribution to the interference that is not parameterized in the model used, and/or detector smearing that is not accounted for in our fit. We also attempt to find an s-wave contribution to the K{pi} mass spectrum by searching for an sp-interference effect. While we find a hint that such an effect exists, we have neither the confidence in the statistics nor systematics in the higher K{pi} mass region to announce an observation. We conclude that it would be a worthwhile study to pursue.

  15. PACSIN1, a Tau-interacting protein, regulates axonal elongation and branching by facilitating microtubule instability.

    PubMed

    Liu, Yingying; Lv, Kaosheng; Li, Zenglong; Yu, Albert C H; Chen, Jianguo; Teng, Junlin

    2012-11-16

    Tau is a major member of the neuronal microtubule-associated proteins. It promotes tubulin assembly and stabilizes axonal microtubules. Previous studies have demonstrated that Tau forms cross-bridges between microtubules, with some particles located on cross-bridges, suggesting that some proteins interact with Tau and might be involved in regulating Tau-related microtubule dynamics. This study reports that PACSIN1 interacts with Tau in axon. PACSIN1 blockade results in impaired axonal elongation and a higher number of primary axonal branches in mouse dorsal root ganglia neurons, which is induced by increasing the binding ability of Tau to microtubules. In PACSIN1-blocked dorsal root ganglia neurons, a greater amount of Tau is inclined to accumulate in the central domain of growth cones, and it promotes the stability of the microtubule network. Taken together, these results suggest that PACSIN1 is an important Tau binding partner in regulating microtubule dynamics and forming axonal plasticity.

  16. Taxol-stabilized microtubules promote the formation of filaments from unmodified full-length Tau in vitro.

    PubMed

    Duan, Aranda R; Goodson, Holly V

    2012-12-01

    Tau is a neuronal protein that stabilizes the microtubule (MT) network, but it also forms filaments associated with Alzheimer's disease. Understanding Tau-MT and Tau-Tau interactions would help to establish Tau function in health and disease. For many years, literature reports on Tau-MT binding behavior and affinity have remained surprisingly contradictory (e.g., 10-fold variation in Tau-MT affinity). Tau-Tau interactions have also been investigated, but whether MTs might affect Tau filament formation is unknown. We have addressed these issues through binding assays and microscopy. We assessed Tau-MT interactions via cosedimentation and found that the measured affinity of Tau varies greatly, depending on the experimental design and the protein concentrations used. To investigate this dependence, we used fluorescence microscopy to examine Tau-MT binding. Strikingly, we found that Taxol-stabilized MTs promote Tau filament formation without characterized Tau-filament inducers. We propose that these novel Tau filaments account for the incongruence in Tau-MT affinity measurements. Moreover, electron microscopy reveals that these filaments appear similar to the heparin-induced Alzheimer's model. These observations suggest that the MT-induced Tau filaments provide a new model for Alzheimer's studies and that MTs might play a role in the formation of Alzheimer's-associated neurofibrillary tangles.

  17. Conformational characterization of human eukaryotic initiation factor 2alpha: a single tryptophan protein.

    PubMed

    Sreejith, R K; Yadav, Viveka Nand; Varshney, Nishant K; Berwal, Sunil K; Suresh, C G; Gaikwad, Sushama M; Pal, Jayanta K

    2009-12-11

    The alpha-subunit of the human eukaryotic initiation factor 2 (heIF2alpha), a GTP binding protein, plays a major role in the initiation of protein synthesis. During various cytoplasmic stresses, eIF2alpha gets phosphorylated by eIF2alpha-specific kinases resulting in inhibition of protein synthesis. The cloned and over expressed heIF2alpha, a protein with a single tryptophan (trp) residue was examined for its conformational characteristics using steady-state and time-resolved tryptophan fluorescence, circular dichroism (CD) and hydrophobic dye binding. The steady-state fluorescence spectrum, fluorescence lifetimes (tau(1)=1.13ns and tau(2)=4.74ns) and solute quenching studies revealed the presence of trp conformers in hydrophobic and differential polar environment at any given time. Estimation of the alpha-helix and beta-sheet content showed: (i) more compact structure at pH 2.0, (ii) distorted alpha-helix and rearranged beta-sheet in presence of 4M guanidine hydrochloride and (iii) retention of more than 50% ordered structure at 95 degrees C. Hydrophobic dye binding to the protein with loosened tertiary structure was observed at pH 2.0 indicating the existence of a molten globule-like structure. These observations indicate the inherent structural stability of the protein under various denaturing conditions.

  18. Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

    PubMed Central

    Harris, Julie A.; Koyama, Akihiko; Maeda, Sumihiro; Ho, Kaitlyn; Devidze, Nino; Dubal, Dena B.; Yu, Gui-Qiu; Masliah, Eliezer; Mucke, Lennart

    2012-01-01

    Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here. PMID:23029293

  19. FTDP-17 mutations in Tau alter the regulation of microtubule dynamics: an "alternative core" model for normal and pathological Tau action.

    PubMed

    LeBoeuf, Adria C; Levy, Sasha F; Gaylord, Michelle; Bhattacharya, Arnab; Singh, Ambuj K; Jordan, Mary Ann; Wilson, Leslie; Feinstein, Stuart C

    2008-12-26

    Mutations affecting either the structure or regulation of the microtubule-associated protein Tau cause neuronal cell death and dementia. However, the molecular mechanisms mediating these deleterious effects remain unclear. Among the most characterized activities of Tau is the ability to regulate microtubule dynamics, known to be essential for proper cell function and viability. Here we have tested the hypothesis that Tau mutations causing neurodegeneration also alter the ability of Tau to regulate the dynamic instability behaviors of microtubules. Using in vitro microtubule dynamics assays to assess average microtubule growth rates, microtubule growth rate distributions, and catastrophe frequencies, we found that all tested mutants possessing amino acid substitutions or deletions mapping to either the repeat or interrepeat regions of Tau do indeed compromise its ability to regulate microtubule dynamics. Further mutational analyses suggest a novel mechanism of Tau regulatory action based on an "alternative core" of microtubule binding and regulatory activities composed of two repeats and the interrepeat between them. In this model, the interrepeat serves as the primary regulator of microtubule dynamics, whereas the flanking repeats serve as tethers to properly position the interrepeat on the microtubule. Importantly, since there are multiple interrepeats on each Tau molecule, there are also multiple cores on each Tau molecule, each with distinct mechanistic capabilities, thereby providing significant regulatory potential. Taken together, the data are consistent with a microtubule misregulation mechanism for Tau-mediated neuronal cell death and provide a novel mechanistic model for normal and pathological Tau action.

  20. Thermodynamics of the interaction between Alzheimer's disease related tau protein and DNA.

    PubMed

    Camero, Sergio; Benítez, María J; Cuadros, Raquel; Hernández, Félix; Avila, Jesús; Jiménez, Juan S

    2014-01-01

    Tau hyperphosphorylation can be considered as one of the hallmarks of Alzheimer's disease and other tauophaties. Besides its well-known role as a microtubule associated protein, Tau displays a key function as a protector of genomic integrity in stress situations. Phosphorylation has been proven to regulate multiple processes including nuclear translocation of Tau. In this contribution, we are addressing the physicochemical nature of DNA-Tau interaction including the plausible influence of phosphorylation. By means of surface plasmon resonance (SPR) we measured the equilibrium constant and the free energy, enthalpy and entropy changes associated to the Tau-DNA complex formation. Our results show that unphosphorylated Tau binding to DNA is reversible. This fact is in agreement with the protective role attributed to nuclear Tau, which stops binding to DNA once the insult is over. According to our thermodynamic data, oscillations in the concentration of dephosphorylated Tau available to DNA must be the variable determining the extent of Tau binding and DNA protection. In addition, thermodynamics of the interaction suggest that hydrophobicity must represent an important contribution to the stability of the Tau-DNA complex. SPR results together with those from Tau expression in HEK cells show that phosphorylation induces changes in Tau protein which prevent it from binding to DNA. The phosphorylation-dependent regulation of DNA binding is analogous to the Tau-microtubules binding inhibition induced by phosphorylation. Our results suggest that hydrophobicity may control Tau location and DNA interaction and that impairment of this Tau-DNA interaction, due to Tau hyperphosphorylation, could contribute to Alzheimer's pathogenesis.

  1. Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy

    PubMed Central

    Puvenna, Vikram; Engeler, Madeline; Banjara, Manoj; Brennan, Chanda; Schreiber, Peter; Dadas, Aaron; Bahrami, Ashkon; Solanki, Jesal; Bandyopadhyay, Anasua; Morris, Jacqueline K.; Bernick, Charles; Ghosh, Chaitali; Bazarian, Jeffrey J.; Janigro, Damir

    2016-01-01

    Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six post mortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE. PMID:26556772

  2. Is phosphorylated tau unique to chronic traumatic encephalopathy? Phosphorylated tau in epileptic brain and chronic traumatic encephalopathy.

    PubMed

    Puvenna, Vikram; Engeler, Madeline; Banjara, Manoj; Brennan, Chanda; Schreiber, Peter; Dadas, Aaron; Bahrami, Ashkon; Solanki, Jesal; Bandyopadhyay, Anasua; Morris, Jacqueline K; Bernick, Charles; Ghosh, Chaitali; Rapp, Edward; Bazarian, Jeffrey J; Janigro, Damir

    2016-01-01

    Repetitive traumatic brain injury (rTBI) is one of the major risk factors for the abnormal deposition of phosphorylated tau (PT) in the brain and chronic traumatic encephalopathy (CTE). CTE and temporal lobe epilepsy (TLE) affect the limbic system, but no comparative studies on PT distribution in TLE and CTE are available. It is also unclear whether PT pathology results from repeated head hits (rTBI). These gaps prevent a thorough understanding of the pathogenesis and clinical significance of PT, limiting our ability to develop preventative and therapeutic interventions. We quantified PT in TLE and CTE to unveil whether a history of rTBI is a prerequisite for PT accumulation in the brain. Six postmortem CTE (mean 73.3 years) and age matched control samples were compared to 19 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years). No history of TBI was present in TLE or control; all CTE patients had a history of rTBI. TLE and CTE brain displayed increased levels of PT as revealed by immunohistochemistry. No age-dependent changes were noted, as PT was present as early as 4 months after birth. In TLE and CTE, cortical neurons, perivascular regions around penetrating pial vessels and meninges were immunopositive for PT; white matter tracts also displayed robust expression of extracellular PT organized in bundles parallel to venules. Microscopically, there were extensive tau-immunoreactive neuronal, astrocytic and degenerating neurites throughout the brain. In CTE perivascular tangles were most prominent. Overall, significant differences in staining intensities were found between CTE and control (P<0.01) but not between CTE and TLE (P=0.08). pS199 tau analysis showed that CTE had the most high molecular weight tangle-associated tau, whereas epileptic brain contained low molecular weight tau. Tau deposition may not be specific to rTBI since TLE recapitulated most of the pathological features of CTE.

  3. Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

    PubMed Central

    Brulois, Kevin; Toth, Zsolt; Wong, Lai-Yee; Feng, Pinghui; Gao, Shou-Jiang; Ensser, Armin

    2014-01-01

    ABSTRACT The downregulation of immune synapse components such as major histocompatibility complex class I (MHC-I) and ICAM-1 is a common viral immune evasion strategy that protects infected cells from targeted elimination by cytolytic effector functions of the immune system. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes two membrane-bound ubiquitin E3 ligases, called K3 and K5, which share the ability to induce internalization and degradation of MHC-I molecules. Although individual functions of K3 and K5 outside the viral genome are well characterized, their roles during the KSHV life cycle are still unclear. In this study, we individually introduced the amino acid-coding sequences of K3 or K5 into a ΔK3 ΔK5 recombinant virus, at either original or interchanged genomic positions. Recombinants harboring coding sequences within the K5 locus showed higher K3 and K5 protein expression levels and more rapid surface receptor downregulation than cognate recombinants in which coding sequences were introduced into the K3 locus. To identify infected cells undergoing K3-mediated downregulation of MHC-I, we employed a novel reporter virus, called red-green-blue-BAC16 (RGB-BAC16), which was engineered to harbor three fluorescent protein expression cassettes: EF1α-monomeric red fluorescent protein 1 (mRFP1), polyadenylated nuclear RNA promoter (pPAN)-enhanced green fluorescent protein (EGFP), and pK8.1-monomeric blue fluorescent protein (tagBFP), marking latent, immediate early, and late viral gene expression, respectively. Analysis of RGB-derived K3 and K5 deletion mutants showed that while the K5-mediated downregulation of MHC-I was concomitant with pPAN induction, the reduction of MHC-I surface expression by K3 was evident in cells that were enriched for pPAN-driven EGFPhigh and pK8.1-driven blue fluorescent protein-positive (BFP+) populations. These data support the notion that immunoreceptor downregulation occurs by a sequential process wherein K5 is critical

  4. Ecological-floristic analysis of soil algae and cyanobacteria on the Tra-Tau and Yurak-Tau Mounts, Bashkiria

    NASA Astrophysics Data System (ADS)

    Bakieva, G. R.; Khaibullina, L. S.; Gaisina, L. A.; Kabirov, R. R.

    2012-09-01

    The species composition of the soil algae and cyanobacteria in the Tra-Tau and Yurak-Tau mountains is represented by 136 species belonging to five phyla: Cyanobacteria (56 species), Chlorophyta (52 species), Xanthophyta (13 species), Bacillariophyta (12 species), and Eustigmatophyta (3 species). Hantzschia amphioxys var. amphioxys, Hantzschia amphioxys var. constricta, Klebsormidium flaccidum, Leptolyngbya foveolarum, Luticola mutica, Navicula minima var. minima, Nostoc punctiforme, Phormidium jadinianum, Phormidium autumnale, and Pinnularia borealis were identified more often than other species. The composition of the algal flora depended on the soil properties; the higher plants also had a significant influence on the species composition of the soil algae.

  5. The mitotic tensegrity guardian tau protects mammary epithelia from katanin-like1-induced aneuploidy

    PubMed Central

    Sudo, Haruka; Nakajima, Kazunori

    2016-01-01

    The microtubule associated-protein tau has been identified as an effective positive prognostic indicator in breast cancer. To explore the physiological function of tau in early carcinogenesis, endogenous tau was knocked down in primary cultured human mammary epithelial cells. This resulted in chromosome-bridging during anaphase followed by micronucleation, both of which were suppressed by a further katanin-like1 knockdown. We also detected that the exogenously expressed katanin-like1 induction of cellular transformation is prevented by exogenous tau in rat fibroblasts. The mutant katanin-like1 (L123V) identified in breast cancer showed an increase in this transformation capacity as well as microtubule severing activity resistant to tau. The tau knockdown resulted in a loss of the kinetochore fibers on which tau is normally localized. This physical fragility was also observed in isolated tau-knockdown mitotic spindles, supporting the relevance of microtubule damage to the onset of transformation. The karyotyping of tau-knockdown cells showed increased frequency of loss of one X chromosome, further suggesting the involvement of tau in breast tumorigenesis. We propose that tau may contribute to tumor progression by protecting spindle microtubules from excess severing by katanin-like1. We also present data indicating that the microtubule-binding octapeptide NAP is a candidate modifier against the tau deficiency in tumor cells. PMID:27447563

  6. A measurement of the ({tau}) polarization at the Z resonance with the DELPHI detector at LEP

    SciTech Connect

    Wong Chan, A.

    1993-07-01

    The polarization of {tau} leptons produced in the reaction e{sup +}e{sup {minus}} {yields} {tau}{sup +}{tau}{sup {minus}} near the peak of the Z{degree} resonance has been measured using a sample of 24904 {tau}{sup +}{tau}{sup {minus}} events, with an estimated background of 1.5%. We have selected 4562 {tau} {yields} e{nu}{bar {nu}} 2218 {tau} {yields} {pi}{nu} and 5133 {tau} {yields} {rho}{nu} candidates. The mean value obtained is P{sub {tau}} = {minus}0.176 {plus_minus} 0.029. This corresponds to a ratio of the neutral current vector to the axial-vector coupling constants of the {tau} lepton of g{sub V}{sup {tau}}/g{sub A}{sup {tau}} = 0.088 {plus_minus} 0.014. This leads to a value of the electroweak mixing angle of sin{sup 2}{theta}{sub W} = 0.2280 {plus_minus} 0.0036. This result is in good agreement with previous measurements of the weak mixing angle from the study of the Z{degree} lineshape and the forward-backward asymmetries in the processes Z{degree} {yields} l{sup +}l{sup {minus}} and Z{degree} {yields} q{bar q}.

  7. Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain.

    PubMed

    Saito, Mariko; Chakraborty, Goutam; Mao, Rui-Fen; Paik, Sun-Mee; Vadasz, Csaba; Saito, Mitsuo

    2010-04-01

    Previous studies indicated that ethanol-induced neurodegeneration in postnatal day 7 (P7) mice, widely used as a model for the fetal alcohol spectrum disorders, was accompanied by glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activation. Presently, we examined whether tau, a microtubule associated protein, is modified by GSK-3beta and caspase-3 in ethanol-treated P7 mouse forebrains. We found that ethanol increased phosphorylated tau recognized by the paired helical filament (PHF)-1 antibody and by the antibody against tau phosphorylated at Ser199. Ethanol also generated tau fragments recognized by an antibody against caspase-cleaved tau (C-tau). C-tau was localized in neurons bearing activated caspase-3 and fragmented nuclei. Over time, cell debris and degenerated projections containing C-tau appeared to be engulfed by activated microglia. A caspase-3 inhibitor partially blocked C-tau formation. Lithium, a GSK-3beta inhibitor, blocked ethanol-induced caspase-3 activation, phosphorylated tau elevation, C-tau formation, and microglial activation. These results indicate that tau is phosphorylated by GSK-3beta and cleaved by caspase-3 during ethanol-induced neurodegeneration in the developing brain.

  8. The Role of Tau in Neurodegenerative Diseases and Its Potential as a Therapeutic Target

    PubMed Central

    2012-01-01

    The abnormal deposition of proteins in and around neurons is a common pathological feature of many neurodegenerative diseases. Among these pathological proteins, the microtubule-associated protein tau forms intraneuronal filaments in a spectrum of neurological disorders. The discovery that dominant mutations in the MAPT gene encoding tau are associated with familial frontotemporal dementia strongly supports abnormal tau protein as directly involved in disease pathogenesis. This and other evidence suggest that tau is a worthwhile target for the prevention or treatment of tau-associated neurodegenerative diseases, collectively called tauopathies. However, it is critical to understand the normal biological roles of tau, the specific molecular events that induce tau to become neurotoxic, the biochemical nature of pathogenic tau, the means by which pathogenic tau exerts neurotoxicity, and how tau pathology propagates. Based on known differences between normal and abnormal tau, a number of approaches have been taken toward the discovery of potential therapeutics. Key questions still remain open, such as the nature of the connection between the amyloid-β protein of Alzheimer's disease and tau pathology. Answers to these questions should help better understand the nature of tauopathies and may also reveal new therapeutic targets and strategies. PMID:24278740

  9. Learning and Memory Deficits upon TAU Accumulation in "Drosophila" Mushroom Body Neurons

    ERIC Educational Resources Information Center

    Mershin, Andreas; Pavlopoulos, Elias; Fitch, Olivia; Braden, Brittany C.; Nanopoulos, Dimitri V.; Skoulakis, Efthimios M. C.

    2004-01-01

    Mutations in the neuronal-specific microtubule-binding protein TAU are associated with several dementias and neurodegenerative diseases. However, the effects of elevated TAU accumulation on behavioral plasticity are unknown. We report that directed expression of wild-type vertebrate and "Drosophila" TAU in adult mushroom body neurons, centers for…

  10. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma–associated ubiquitin ligase K5

    PubMed Central

    Nanes, Benjamin A.; Grimsley-Myers, Cynthia M.; Cadwell, Chantel M.; Robinson, Brian S.; Lowery, Anthony M.; Vincent, Peter A.; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P.

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability. PMID:27798235

  11. p120-catenin regulates VE-cadherin endocytosis and degradation induced by the Kaposi sarcoma-associated ubiquitin ligase K5.

    PubMed

    Nanes, Benjamin A; Grimsley-Myers, Cynthia M; Cadwell, Chantel M; Robinson, Brian S; Lowery, Anthony M; Vincent, Peter A; Mosunjac, Marina; Früh, Klaus; Kowalczyk, Andrew P

    2017-01-01

    Vascular endothelial (VE)-cadherin undergoes constitutive internalization driven by a unique endocytic motif that also serves as a p120-catenin (p120) binding site. p120 binding masks the motif, stabilizing the cadherin at cell junctions. This mechanism allows constitutive VE-cadherin endocytosis and recycling to contribute to adherens junction dynamics without resulting in junction disassembly. Here we identify an additional motif that drives VE-cadherin endocytosis and pathological junction disassembly associated with the endothelial-derived tumor Kaposi sarcoma. Human herpesvirus 8, which causes Kaposi sarcoma, expresses the MARCH family ubiquitin ligase K5. We report that K5 targets two membrane-proximal VE-cadherin lysine residues for ubiquitination, driving endocytosis and down-regulation of the cadherin. K5-induced VE-cadherin endocytosis does not require the constitutive endocytic motif. However, K5-induced VE-cadherin endocytosis is associated with displacement of p120 from the cadherin, and p120 protects VE-cadherin from K5. Thus multiple context-dependent signals drive VE-cadherin endocytosis, but p120 binding to the cadherin juxtamembrane domain acts as a master regulator guarding cadherin stability.

  12. Detection of tau neutrinos by imaging air Cherenkov telescopes

    NASA Astrophysics Data System (ADS)

    Góra, D.; Bernardini, E.

    2016-09-01

    This paper investigates the potential to detect tau neutrinos in the energy range of 1-1000 PeV searching for very inclined showers with imaging Cherenkov telescopes. A neutrino induced tau lepton escaping from the Earth may decay and initiate an air shower which can be detected by a fluorescence or Cherenkov telescope. We present here a study of the detection potential of Earth-skimming neutrinos taking into account neutrino interactions in the Earth crust, local matter distributions at various detector sites, the development of tau-induced showers in air and the detection of Cherenkov photons with IACTs. We analyzed simulated shower images on the camera focal plane and implemented generic reconstruction chains based on Hillas parameters. We find that present IACTs can distinguish air showers induced by tau neutrinos from the background of hadronic showers in the PeV-EeV energy range. We present the neutrino trigger efficiency obtained for a few configurations being considered for the next-generation Cherenkov telescopes, i.e. the Cherenkov Telescope Array. Finally, for a few representative neutrino spectra expected from astrophysical sources, we compare the expected event rates at running IACTs to what is expected for the dedicated IceCube neutrino telescope.

  13. Aggregation propensity of critical regions of the protein Tau

    NASA Astrophysics Data System (ADS)

    Muthee, Micaiah; Ahmed, Azka; Larini, Luca

    The Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, which eventually leads to the ability to not able to carry out the simplest tasks. The Alzheimer's disease is characterized by the formation of protein aggregates both within and outside of the brain's cells, the neurons. Within the neurons, the aggregation of the protein tau leads to the destruction of the microtubules in the axon of the neuron. Tau belongs to a group of proteins referred to as Microtubule-Associated Proteins. It is extremely flexible and is classified as an intrinsically unstructured protein due to its low propensity to form secondary structure. Tau promotes tubulin assembly into microtubules thereby stabilizing the cytoskeleton of the axon of the neurons. The microtubule binding region of tau consists of 4 pseudo-repeats. In this study, we will focus on the aggregation propensity of two fragments. In this study we will focus on the PHF43 fragment that contains the third pseudo-repeat and has been shown experimentally to aggregate readily. Another fragment that contains the second pseudo-repeat will be considered as well. Mutations in this region are associated with various form of dementia and for this reason we will consider the mutant P301L.

  14. Signature of an aggregation-prone conformation of tau

    NASA Astrophysics Data System (ADS)

    Eschmann, Neil A.; Georgieva, Elka R.; Ganguly, Pritam; Borbat, Peter P.; Rappaport, Maxime D.; Akdogan, Yasar; Freed, Jack H.; Shea, Joan-Emma; Han, Songi

    2017-03-01

    The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6(*) regions dramatically extend to distances commensurate with extended β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-strand conformational state of PHF6(*) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions.

  15. Signature of an aggregation-prone conformation of tau

    PubMed Central

    Eschmann, Neil A.; Georgieva, Elka R.; Ganguly, Pritam; Borbat, Peter P.; Rappaport, Maxime D.; Akdogan, Yasar; Freed, Jack H.; Shea, Joan-Emma; Han, Songi

    2017-01-01

    The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6(*) regions dramatically extend to distances commensurate with extended β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-strand conformational state of PHF6(*) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions. PMID:28303942

  16. Microtubules (tau) as an emerging therapeutic target: NAP (davunetide).

    PubMed

    Gozes, Illana

    2011-01-01

    This review focuses on the discovery of activity-dependent neuroprotective protein (ADNP) and the ensuing discovery of NAP (davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration. NAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (davunetide) interacted with microtubules, protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo. NAP (davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity and synapse formation by increasing synaptophysin expression. NAP (davunetide) protection against neurodegeneration has recently been shown to extend to katanin-related microtubule disruption under conditions of tau deficiencies. In conclusion, NAP (davunetide) provided potent neuroprotection in a broad range of neurodegenerative models, protecting the neuroglial cytoskeleton in vitro and inhibiting tau pathology (tauopathy) in vivo. Based on these extensive preclinical results, davunetide (NAP) is now being evaluated in a Phase II/III study of the tauopathy, progressive supranuclear palsy (PSP); (Allon Therapeutics Inc.).

  17. Variances and Covariances of Kendall's Tau and Their Estimation.

    ERIC Educational Resources Information Center

    Cliff, Norman; Charlin, Ventura

    1991-01-01

    Variance formulas of H. E. Daniels and M. G. Kendall (1947) are generalized to allow for the presence of ties and variance of the sample tau correlation. Applications of these generalized formulas are discussed and illustrated using data from a 1965 study of contraceptive use in 15 developing countries. (SLD)

  18. Structural Impact of Tau Phosphorylation at Threonine 231.

    PubMed

    Schwalbe, Martin; Kadavath, Harindranath; Biernat, Jacek; Ozenne, Valery; Blackledge, Martin; Mandelkow, Eckhard; Zweckstetter, Markus

    2015-08-04

    Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neurodegenerative diseases. The high flexibility of Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding (225)KVAVVR(230) motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins.

  19. Multinomial Tau-Leaping Method for Stochastic Kinetic Simulations

    SciTech Connect

    Pettigrew, Michel F.; Resat, Haluk

    2007-02-28

    We introduce the multinomial tau-leaping (MtL) method, an improved version of the binomial tau-leaping method, for general reaction networks. Improvements in efficiency are achieved in several ways. Firstly, tau-leaping steps are determined simply and efficiently using a-prior information. Secondly, networks are partitioned into closed groups of reactions and corresponding reactants in which no group reactant or reaction is found in any other group. Thirdly, product formation is factored into upper bound estimation of the number of times a particular reaction occurs. Together, these features allow for larger time steps where the numbers of reactions occurring simultaneously in a multi-channel manner are estimated accurately using a multinomial distribution. Using a wide range of test case problems of scientific and practical interest involving cellular processes, such as epidermal growth factor receptor signaling and lactose operon model incorporating gene transcription and translation, we show that tau-leaping based methods like the MtL algorithm can significantly reduce the number of simulation steps thus increasing the numerical efficiency over the exact stochastic simulation algorithm by orders of magnitude. Furthermore, the simultaneous multi-channel representation capability of the MtL algorithm makes it a candidate for FPGA implementation or for parallelization in parallel computing environments.

  20. Recombinant Escherichia coli K5 strain with the deletion of waaR gene decreases the molecular weight of the heparosan capsular polysaccharide.

    PubMed

    Huang, Haichan; Liu, Xiaobo; Lv, Shencong; Zhong, Weihong; Zhang, Fuming; Linhardt, Robert J

    2016-09-01

    Heparosan, the capsular polysaccharide of Escherichia coli K5 having a carbohydrate backbone similar to that of heparin, has become a potential precursor for bioengineering heparin. In the heparosan biosynthesis pathway, the gene waaR encoding α-1-, 2- glycosyltransferase catalyze s the third glucosyl residues linking to the oligosaccharide chain. In the present study, a waaR deletion mutant of E. coli K5 was constructed. The mutant showed improvement of capsule polysaccharide yield. It is interesting that the heparosan molecular weight of the mutant is reduced and may become more suitable as a precursor for the production of low molecular weight heparin derived from the wild-type K5 capsular polysaccharide.

  1. Tau and muon lepton flavor violations in the littlest Higgs model with T parity

    SciTech Connect

    Goto, Toru; Okada, Yasuhiro; Yamamoto, Yasuhiro

    2011-03-01

    Lepton flavor violation in {tau} and {mu} processes is studied in the littlest Higgs model with T parity. We consider various asymmetries defined in polarized {tau} and {mu} decays. Correlations among branching ratios and asymmetries are shown in the following lepton flavor violation processes: {mu}{sup +}{yields}e{sup +}{gamma}, {mu}{sup +}{yields}e{sup +}e{sup +}e{sup -}, {mu}{sup -}A{yields}e{sup -}A (A=Al, Ti, Au, and Pb), {tau}{sup +}{yields}{mu}{sup +}{gamma}, {tau}{sup +}{yields}{mu}{sup +}{mu}{sup +}{mu}{sup -}, {tau}{sup +}{yields}{mu}{sup +}e{sup +}e{sup -}, {tau}{sup +}{yields}{mu}{sup +}P (P={pi}{sup 0}, {eta} and {eta}{sup '}), {tau}{sup +}{yields}{mu}{sup +}V (V={rho}{sup 0}, {omega} and {phi}), {tau}{sup +}{yields}e{sup +}{gamma}, {tau}{sup +}{yields}e{sup +}e{sup +}e{sup -}, {tau}{sup +}{yields}e{sup +}{mu}{sup +}{mu}{sup -}, {tau}{sup +}{yields}e{sup +}P, {tau}{sup +}{yields}e{sup +}V, {tau}{sup +}{yields}{mu}{sup +}{mu}{sup +}e{sup -} and {tau}{sup +}{yields}e{sup +}e{sup +}{mu}{sup -}. It is shown that large parity asymmetries and time-reversal asymmetries are allowed in {mu}{sup +}{yields}e{sup +}e{sup +}e{sup -}. For {tau} lepton flavor violation processes, sizable asymmetries are possible reflecting characteristic chirality structure of lepton flavor violating interactions in this model.

  2. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and Progressive Supranuclear Palsy

    PubMed Central

    Wagshal, Dana; Sankaranarayanan, Sethu; Guss, Valerie; Hall, Tracey; Berisha, Flora; Lobach, Iryna; Karydas, Anna; Voltarelli, Lisa; Scherling, Carole; Heuer, Hilary; Tartaglia, Maria Carmela; Miller, Zachary; Coppola, Giovanni; Ahlijanian, Michael; Soares, Holly; Kramer, Joel H; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Meredith, Jere; Boxer, Adam L

    2014-01-01

    Background Elevated CSF tau is considered a biomarker of neuronal injury in newly developed Alzheimer’s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 PSP patients participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables. Results PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients. Conclusions CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury. PMID:24899730

  3. PHOSPHORYLATED TAU: CANDIDATE BIOMARKER FOR AMYOTROPHIC LATERAL SCLEROSIS

    PubMed Central

    Grossman, Murray; Elman, Lauren; McCluskey, Leo; McMillan, Corey T.; Boller, Ashley; Powers, John; Rascovsky, Katya; Hu, William; Shaw, Les; Irwin, David J.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2014-01-01

    IMPORTANCE An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility is necessary. OBJECTIVE We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN Case-control study. SETTING Academic medical center. PARTICIPANTS 51 individuals with ALS and 23 individuals with a disorder associated with a four-repeat tauopathy (4R-tau). MAIN OUTCOME MEASURE CSF level of tau phosophorylated at threonine 181 (ptau), and ratio of ptau to total tau (ttau). RESULTS Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 (85.7%) of 21 cases with autopsy-proven or genetically-determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity such as Mini Mental State Exam (n=51) and ALS Functional Rating Scale-Revised (n=42), and regression analyses related ptau:ttau to MRI (n=10) evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex. CONCLUSIONS AND RELEVANCE CSF ptau:ttau may be a candidate biomarker to provide objective support for the diagnosis of ALS. PMID:24492862

  4. Induction of intracellular tau aggregation is promoted by α-synuclein seeds, and provides novel insights into the hyperphosphorylation of tau

    PubMed Central

    Waxman, Elisa A.; Giasson, Benoit I.

    2011-01-01

    Intracytoplasmic proteinaceous inclusions, primarily composed of tau or α-synuclein (α-syn), are predominant pathological features of Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. However, the co-existence of these pathological aggregates is identified in many neurodegenerative disorders, including spectrum disorders of AD and PD. While α-syn can spontaneously polymerize into amyloidogenic fibrils, in vitro, tau polymerization requires an inducing agent. The current study presents a human-derived cellular model, in which recombinant, pre-formed α-syn fibrils cross-seed intracellular tau to promote the formation of neurofibrillary tangle-like aggregates. These aggregates were hyperphosphorylated, Triton-insoluble, and thioflavin S-positive, either co-mingling with endogenously expressed α-syn aggregates, or induced by only exogenously applied recombinant α-syn fibrils. Further, filamentous, amyloidogenic tau took over the cellular soma, displacing the nucleus and isolating or displacing organelles, likely preventing cellular function. While a significant proportion of wild-type tau formed these cellular inclusions, the P301L mutation in tau increased aggregation propensity resulting from α-syn seeds to over 50% of total tau protein. The role of phosphorylation on the development of these tau aggregates was investigated by co-expressing glycogen synthase kinase 3 beta or MAP/microtubule affinity-regulating kinase 2. Expression of either kinase inhibited the formation of α-syn-induced tau aggregates. Analyses of phosphorylation sites suggest that multiple complex factors may be associated with this effect, and that Triton-soluble versus Triton-insoluble tau may be independently targeted by kinases. The current work not only provides an exceptional cellular model of tau pathology, but also examines α-syn-induced tau inclusion formation and provides novel insights into hyperphosphorylation observed in disease. PMID:21613474

  5. VizieR Online Data Catalog: CaII and Hα data for dK5/dM4 stars (Houdebine, 2012)

    NASA Astrophysics Data System (ADS)

    Houdebine, E. R.

    2013-03-01

    We use 665 high-resolution spectra for 60 different dM4 stars and 1088 high-resolution spectra for 97 different dK5 stars from the European Southern Observatory (ESO) and Observatoire de Haute Provence (OHP) data bases. We present 179 new measurements of the CaII resonance lines and 615 new measurements of the Hα line for dM4 stars. We also present 701 new measurements of the CaII resonance lines and 1088 new measurements of the Hα line for dK5 stars. We also compiled other measurements available in the literature. (6 data files).

  6. A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau.

    PubMed

    Ishiguro, K; Ihara, Y; Uchida, T; Imahori, K

    1988-09-01

    From rat brain microtubule proteins, we purified a protein kinase that phosphorylated tau, one of microtubule-associated proteins. The electrophoretic mobility of the phosphorylated tau on SDS-polyacrylamide gel decreased. The enzyme was not activated by cyclic nucleotides, calmodulin, or phospholipids, and was inhibited by the calcium ions. The kinase bound to tau. The phosphorylation of tau was stimulated by tubulin under the condition of microtubule formation. From these results we propose an idea that the phosphorylation could occur concomitantly with microtubule formation in the brain. Human tau phosphorylated by the kinase carried an epitope of the paired helical filaments that accumulate in the brain in Alzheimer's disease.

  7. Ab initio alpha-alpha scattering.

    PubMed

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A; Luu, Thomas; Meißner, Ulf-G

    2015-12-03

    Processes such as the scattering of alpha particles ((4)He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei--nuclei with even and equal numbers of protons and neutrons--is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the 'adiabatic projection method' to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  8. Ab initio alpha-alpha scattering

    NASA Astrophysics Data System (ADS)

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A.; Luu, Thomas; Meißner, Ulf-G.

    2015-12-01

    Processes such as the scattering of alpha particles (4He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei—nuclei with even and equal numbers of protons and neutrons—is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the ‘adiabatic projection method’ to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  9. Production of O-GlcNAc Modified Recombinant Tau in E. coli and Detection of Ser400 O-GlcNAc Tau In Vivo.

    PubMed

    Yuzwa, Scott A; Vocadlo, David J

    2017-01-01

    Assembly of the microtubule-associated protein tau (tau) into paired helical filaments that ultimately give rise to neurofibrillary tangles (NFTs) makes up one half of the two hallmark pathologies of Alzheimer's disease (AD). Tau has been shown to be modified with O-linked N-acetylglucosamine residues (O-GlcNAc), which is the modification of serine and threonine residues of nucleocytoplasmic proteins with N-acetyl-D-glucosamine (GlcNAc) moieties. Increasing O-GlcNAc in mouse models of tauopathy has been shown to hinder the progression of symptoms in these mice and impair the aggregation of tau into NFTs. In order to study how O-GlcNAc on tau may contribute to the protective effects observed in tauopathy mouse models, it is beneficial to study O-GlcNAc modified tau in vitro. Here we describe a method for producing, purifying and enriching recombinant tau that is O-GlcNAc modified. These methods have enabled the identification of O-GlcNAc modification sites on tau including Ser400. We further describe the detection of Ser400 O-GlcNAc on tau from brain lysates.

  10. Circumstellar jets and disk of DL Tau and CW Tau observed with HST/STIS and the GSFC Fabry-Perot imager

    NASA Technical Reports Server (NTRS)

    Grady, Carol; Woodgate, Bruce; Kimble, Randy; Palunas, Povilas; Oegerle, William R. (Technical Monitor)

    2002-01-01

    The pre-main sequence T Tauri stars DL Tau and CW Tau were observed with Hubble Space Telescope/Space Telescope Imaging Spectrograph (HST/STIS) and the Goddard Fabry-Perot Imager at the Apache Point 3.5-m telescope in their coronagraphic modes. The STIS observation of DL Tau shows a circumstellar disk with a dark ring, and the jet with structure along the length, and a faint counter-jet. On CW Tau, STIS shows a jet with a bright blob about 4 arcsec away, and the Fabry-Perot shows the jet extended in both directions in [SII] to 60 and 90 arcsec from the star.

  11. Altered phosphorylation of. tau. protein in heat-shocked rats and patients with Alzheimer disease

    SciTech Connect

    Papasozomenos, S.C.; Yuan Su Baylor College of Medicine, Houston, TX )

    1991-05-15

    Six hours after heat shocking 2- to 3-month-old male and female Sprague-Dawley rats at 42C for 15 min, the authors analyzed {tau} protein immunoreactivity in SDS extracts of cerebrums and peripheral nerves by using immunoblot analysis and immunohistochemistry with the anti-{tau} monoclonal antibody Tau-1, which recognizes a phosphate-dependent nonphosphorylated epitope, and with {sup 125}I-labeled protein A. In the cerebal extracts, the authors found altered phosphorylation of {tau} in heat-shocked females, characterized by a marked reduction in the amount of nonphosphorylated {tau}, a doubling of the ratio of total (phosphorylated plus nonphosphorylated) {tau} to nonphosphorylated {tau}, and the appearance of the slowest moving phosphorylated {tau} polypeptide (68 kDa). Similar, but milder, changes were observed in male rats. Quantitative immunoblot analysis of cortex and the underlying white matter with Tau-1 and {sup 125}I-labeled protein A showed that the amount of phosphorylated {tau} progressively increased in the Alzheimer disease-affected cerebral cortex, while concurrently a proportionally lesser amount of {tau} entered the white matter axons. The similar findings for the rat heat-shock model and Alzheimer disease suggest that life stressors may play a role in the etiopathogenesis of Alzheimer's disease.

  12. Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology.

    PubMed

    Belarbi, Karim; Burnouf, Sylvie; Fernandez-Gomez, Francisco-Jose; Laurent, Cyril; Lestavel, Sophie; Figeac, Martin; Sultan, Audrey; Troquier, Laetitia; Leboucher, Antoine; Caillierez, Raphaëlle; Grosjean, Marie-Eve; Demeyer, Dominique; Obriot, Hélène; Brion, Ingrid; Barbot, Bérangère; Galas, Marie-Christine; Staels, Bart; Humez, Sandrine; Sergeant, Nicolas; Schraen-Maschke, Susanna; Muhr-Tailleux, Anne; Hamdane, Malika; Buée, Luc; Blum, David

    2011-08-01

    Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.

  13. Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis.

    PubMed

    Zhao, Yingjun; Tseng, I-Chu; Heyser, Charles J; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Zheng, Qiuyang; Huang, Timothy; Wang, Xin; Arslan, Pharhad E; Chakrabarty, Paramita; Wu, Chengbiao; Bu, Guojun; Mobley, William C; Zhang, Yun-Wu; St George-Hyslop, Peter; Masliah, Eliezer; Fraser, Paul; Xu, Huaxi

    2015-09-02

    Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects.

  14. The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics.

    PubMed

    Pritchard, Susanne M; Dolan, Philip J; Vitkus, Alisa; Johnson, Gail V W

    2011-08-01

    It has been almost 25 years since the initial discovery that tau was the primary component of the neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain. Although AD is defined by both β-amyloid (Aβ) pathology (Aβ plaques) and tau pathology (NFTs), whether or not tau played a critical role in disease pathogenesis was a subject of discussion for many years. However, given the increasing evidence that pathological forms of tau can compromise neuronal function and that tau is likely an important mediator of Aβ toxicity, there is a growing awareness that tau is a central player in AD pathogenesis. In this review we begin with a brief history of tau, then provide an overview of pathological forms of tau, followed by a discussion of the differential degradation of tau by either the proteasome or autophagy and possible mechanisms by which pathological forms of tau may exert their toxicity. We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau's role in AD.

  15. Calpain-Mediated Tau Cleavage: A Mechanism Leading to Neurodegeneration Shared by Multiple Tauopathies

    PubMed Central

    Ferreira, Adriana; Bigio, Eileen H

    2011-01-01

    Tau dysfunction has been associated with a host of neurodegenerative diseases called tauopathies. These diseases share, as a common pathological hallmark, the presence of intracellular aggregates of hyperphosphorylated tau in affected brain areas. Aside from tau hyperphosphorylation, little is known about the role of other posttranslational modifications in tauopathies. Recently, we obtained data suggesting that calpain-mediated tau cleavage leading to the generation of a neurotoxic tau fragment might play an important role in Alzheimer’s disease. In the current study, we assessed the presence of this tau fragment in several tauopathies. Our results show high levels of the 17-kDa tau fragment and enhanced calpain activity in the temporal cortex of AD patients and in brain samples obtained from patients with other tauopathies. In addition, our data suggest that this fragment could partially inhibit tau aggregation. Conversely, tau aggregation might prevent calpain-mediated cleavage, establishing a feedback circuit that might lead to the accumulation of this toxic tau fragment. Collectively, these data suggest that the mechanism underlying the generation of the 17-kDa neurotoxic tau fragment might be part of a conserved pathologic process shared by multiple tauopathies. PMID:21442128

  16. Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models

    PubMed Central

    Malmanche, Nicolas; Dourlen, Pierre; Gistelinck, Marc; Demiautte, Florie; Link, Nichole; Dupont, Cloé; Vanden Broeck, Lies; Werkmeister, Elisabeth; Amouyel, Philippe; Bongiovanni, Antonino; Bauderlique, Hélène; Moechars, Dieder; Royou, Anne; Bellen, Hugo J.; Lafont, Frank; Callaerts, Patrick; Lambert, Jean-Charles; Dermaut, Bart

    2017-01-01

    Tau-mediated neurodegeneration in Alzheimer’s disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development. PMID:28112163

  17. alpha-Hexachlorocyclohexane (alpha-HCH)

    Integrated Risk Information System (IRIS)

    alpha - Hexachlorocyclohexane ( alpha - HCH ) ; CASRN 319 - 84 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Ass

  18. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy.

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; Seripa, Davide; Imbimbo, Bruno P; Lozupone, Madia; Santamato, Andrea; Tortelli, Rosanna; Galizia, Ilaria; Prete, Camilla; Daniele, Antonio; Pilotto, Alberto; Greco, Antonio; Logroscino, Giancarlo

    2016-09-01

    Pharmacological manipulation of tau protein in Alzheimer's disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer's disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.

  19. H{alpha} ABSORPTION IN TRANSITING EXOPLANET ATMOSPHERES

    SciTech Connect

    Christie, Duncan; Arras, Phil; Li Zhiyun E-mail: pla7y@virginia.edu

    2013-08-01

    Absorption of stellar H{alpha} by the upper atmosphere of the planet HD 189733b has recently been detected by Jensen et al. Motivated by this observation, we have developed a model for atomic hydrogen in the n = 2 state and compared the resulting H{alpha} line profile to the observations. The model atmosphere is in hydrostatic balance, as well as thermal and photoionization equilibrium. Collisional and radiative transitions are included in the determination of the n = 2 state level population. We find that H{alpha} absorption is dominated by an optical depth {tau} {approx} 1 shell, composed of hydrogen in the metastable 2s state that is located below the hydrogen ionization layer. The number density of the 2s state within the shell is found to vary slowly with radius, while that of the 1s state falls rapidly. Thus while the Ly{alpha} absorption, for a certain wavelength, occurs inside a relatively well defined impact parameter, the contribution to H{alpha} absorption is roughly uniform over the entire atomic hydrogen layer. The model can approximately reproduce the observed Ly{alpha} and H{alpha} integrated transit depths for HD 189733b by using an ionization rate enhanced over that expected for the star by an order of magnitude. For HD 209458b, we are unable to explain the asymmetric H{alpha} line profile observed by Jensen et al., as the model produces a symmetric line profile with transit depth comparable to that of HD 189733b. In an appendix, we study the effect of the stellar Ly{alpha} absorption on the net cooling rate.

  20. The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging.

    PubMed

    Gordon, Brian A; Friedrichsen, Karl; Brier, Matthew; Blazey, Tyler; Su, Yi; Christensen, Jon; Aldea, Patricia; McConathy, Jonathan; Holtzman, David M; Cairns, Nigel J; Morris, John C; Fagan, Anne M; Ances, Beau M; Benzinger, Tammie L S

    2016-08-01

    The two primary molecular pathologies in Alzheimer's disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices

  1. Alpha Hydroxy Acids

    MedlinePlus

    ... Cosmetics Home Cosmetics Products & Ingredients Ingredients Alpha Hydroxy Acids Share Tweet Linkedin Pin it More sharing options ... for Industry: Labeling for Cosmetics Containing Alpha Hydroxy Acids The following information is intended to answer questions ...

  2. Laying the Foundation for Successful Non-Academic Writing: Professional Communication Principles in the K-5 Curricula of the McKinney Independent School District

    ERIC Educational Resources Information Center

    Trevino, Marlea

    2009-01-01

    Traditionally, K-5 students' writing has had a primarily academic aim--to help students master concepts and express themselves. Even if students take a professional writing course later, they typically do not have the opportunity to practice--over the long period of time mastery requires--the non-academic writing skills they will be required to…

  3. Expanding the Role of K-5 Science Instruction in Educational Reform: Implications of an Interdisciplinary Model for Integrating Science and Reading

    ERIC Educational Resources Information Center

    Romance, Nancy R.; Vitale, Michael R.

    2012-01-01

    Addressed is the current practice in educational reform of reducing time for science instruction in favor of traditional reading/language arts instruction. In contrast, presented is an evidence-based rationale for increasing instructional time for K-5 science instruction as an educational reform initiative. Overviewed are consensus…

  4. Wake County Public School System K-5 Assessment Results: 2009-10. Measuring Up. E&R Report No. 10.19

    ERIC Educational Resources Information Center

    Rhea, Anisa

    2010-01-01

    Moderate to high percentages of Wake County Public School (WCPSS) students demonstrated grade-level performance on K-5 assessments in 2009-10. Results indicate very slight changes from prior years. The percentage of students proficient in reading book level and mathematics strands increased very slightly since 2007-08. Modest declines in…

  5. Modeling Math Growth Trajectory--An Application of Conventional Growth Curve Model and Growth Mixture Model to ECLS K-5 Data

    ERIC Educational Resources Information Center

    Lu, Yi

    2016-01-01

    To model students' math growth trajectory, three conventional growth curve models and three growth mixture models are applied to the Early Childhood Longitudinal Study Kindergarten-Fifth grade (ECLS K-5) dataset in this study. The results of conventional growth curve model show gender differences on math IRT scores. When holding socio-economic…

  6. Fluorescence quenching and time-resolved fluorescence studies of alpha-mannosidase from Aspergillus fischeri (NCIM 508).

    PubMed

    Shashidhara, K S; Gaikwad, Sushama M

    2007-11-01

    Apart from the vital role in glycoprotein biosynthesis and degradation, alpha-mannosidase is currently an important therapeutic target for the development of anticancer agents. Fluorescence quenching and time-resolved fluorescence of alpha-mannosidase, a multitryptophan protein from Aspergillus fischeri were carried out to investigate the tryptophan environment. The tryptophans were found to be differentially exposed to the solvent and were not fully accessible to the neutral quencher indicating heterogeneity in the environment. Quenching of the fluorescence by acrylamide was collisional. Surface tryptophans were found to have predominantly positively charged amino acids around them and differentially accessible to the ionic quenchers. Denaturation led to more exposure of tryptophans to the solvent and consequently in the significant increase in quenching with all the quenchers. The native enzyme showed two different lifetimes, tau (1) (1.51 ns) and tau (2) (5.99 ns). The average lifetime of the native protein (tau) (3.187 ns) was not affected much after denaturation (tau) (3.219 ns), while average lifetime of the quenched protein samples was drastically reduced (1.995 ns for acrylamide and 1.537 ns for iodide). This is an attempt towards the conformational studies of alpha-mannosidase.

  7. The Alpha Centauri System.

    ERIC Educational Resources Information Center

    Soderblom, David R.

    1987-01-01

    Describes the Alpha Centauri star system, which is the closest star system to the sun. Discusses the difficulties associated with measurements involving Alpha Centauri, along with some of the recent advances in stellar seismology. Raises questions about the possibilities of planets around Alpha Centauri. (TW)

  8. Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration.

    PubMed

    Albayram, Onder; Herbert, Megan K; Kondo, Asami; Tsai, Cheng-Yu; Baxley, Sean; Lian, Xiaolan; Hansen, Madison; Zhou, Xiao Zhen; Lu, Kun Ping

    2016-01-01

    One of the two common hallmark lesions of Alzheimer's disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.

  9. Tau Positron Emission Tomography (PET) Imaging: Past, Present, and Future.

    PubMed

    Ariza, Manuela; Kolb, Hartmuth C; Moechars, Dieder; Rombouts, Frederik; Andrés, José Ignacio

    2015-06-11

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation of the density and neocortical spread of neurofibrillary tangles (NFTs) with clinical AD disease progression offers an opportunity for the early diagnosis and staging using a noninvasive imaging technique such as positron emission tomography (PET). Thus, PET imaging of NFTs not only holds promise as a diagnostic tool but also may enable the development of disease modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to the identification of high affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.

  10. Reconstruction and identification of tau leptons in CMS

    NASA Astrophysics Data System (ADS)

    Romeo, Francesco

    2016-11-01

    Tau leptons constitute an important experimental signature for analyses at the CERN LHC related to Higgs boson, Standard Model, and beyond the Standard Model measurements. We describe the algorithm used by the CMS experiment to reconstruct and identify decays of tau leptons into hadrons and a neutrino during Run 1 of the CERN LHC. The performance of the algorithm is studied in proton-proton collisions recorded at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 19.7 fb-1. The algorithm achieves an identification efficiency of typically 50-60%, with misidentification rates for quark and gluon jets, electrons and muons that vary between per mille and percent levels.

  11. Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice.

    PubMed

    Baker, Siân; Polanco, Juan Carlos; Götz, Jϋrgen

    2016-10-04

    In Alzheimer's disease, the distribution of neurofibrillary tangles, a histological hallmark comprised of phosphorylated forms of the protein tau, follows a distinct pattern through anatomically connected brain regions. The well-documented correlation between the severity of tau pathology and disease progression implies a prion-like seeding and spreading mechanism for tau. Experimentally, this has been addressed in transgenic mice by the injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, that were shown to behave like seeds, accelerating tau pathology and tangle formation in predisposed mice. More specifically, in vivo data suggest that brain lysates from mice harboring the P301S mutation of tau can seed protein aggregation when injected into the hippocampi of human wild-type tau transgenic ALZ17 mice. Here, we compared the seeding potential of lysates and extracellular vesicles enriched for exosomes (EVs) from wild-type and human P301L tau transgenic rTg4510 mouse brains. We show that transgenic EVs cause increased tau phosphorylation and soluble oligomer formation in a manner comparable to that of freely available proteins in brain lysates, a prerequisite for the formation of mature protein aggregates.

  12. Tau as a Potential Control Variable for Visually Guided Braking

    ERIC Educational Resources Information Center

    Rock, Paul B.; Harris, Mike G.

    2006-01-01

    D. N. Lee (1976) described a braking strategy based on optical expansion in which the driver brakes so that the target's time-to-contact declines around a constant slope in the range -0.5 less than or equal to tau less than 0. The present results from a series of braking simulations confirm and extend earlier reports (E. H. Yilmaz & W. H. Warren,…

  13. Defining the Pathophysiological Role of Tau in Experimental TBI

    DTIC Science & Technology

    2015-10-01

    pathway that is both preferentially vulnerable in early-stage AD and critically important for long-term memory . The model confines expression of...function of the hippocampus after TBI, and whether TBI exacerbates ongoing tauopathy to promote a chronic neurodegenerative condition. In addition...evidence that mild TBI impairs hippocampus -dependent spatial learning acutely post-injury, and pathological human tau does not exacerbate this

  14. The Weak-Line T Tauri Star V410 Tau

    DTIC Science & Technology

    2003-01-01

    of the lightcurve with high precision. Joining the result with previous data we provide a new estimate for the dominant periodicity of V410 Tau...the minimum in the optical lightcurve over such a long timescale emphasizes the extraordinary stability of the largest spot. This is confirmed by...sequence star on which an activity cycle is detected. Two X-ray pointings were carried out with the Chandra satellite simultaneously with the optical

  15. Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function.

    PubMed

    Oaks, Adam W; Frankfurt, Maya; Finkelstein, David I; Sidhu, Anita

    2013-01-01

    Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT) to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.

  16. Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation.

    PubMed

    Mead, Emma; Kestoras, Dimitra; Gibson, Yolanda; Hamilton, Lucy; Goodson, Ross; Jones, Sophie; Eversden, Sarah; Davies, Peter; O'Neill, Michael; Hutton, Michael; Szekeres, Philip; Wolak, Joanna

    2016-10-18

    Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer's disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau's propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression.

  17. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes.

    PubMed

    Santa-Maria, Ismael; Varghese, Merina; Ksiezak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M

    2012-06-08

    Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology.

  18. Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes*

    PubMed Central

    Santa-Maria, Ismael; Varghese, Merina; Ksiȩżak-Reding, Hanna; Dzhun, Anastasiya; Wang, Jun; Pasinetti, Giulio M.

    2012-01-01

    Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology. PMID:22496370

  19. Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis.

    PubMed

    George, Roshni C; Lew, John; Graves, Donald J

    2013-01-01

    Abnormal modifications in tau such as hyperphosphorylation, oxidation, and glycation interfere with its interaction with microtubules leading to its dissociation and self-aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease (AD). Previously we reported that an aqueous extract of cinnamon has the ability to inhibit tau aggregation in vitro and can even induce dissociation of tangles isolated from AD brain. In the present study, we carried out investigations with cinnamaldehyde (CA) and epicatechin (EC), two components of active cinnamon extract. We found that CA and the oxidized form of EC (ECox) inhibited tau aggregation in vitro and the activity was due to their interaction with the two cysteine residues in tau. Mass spectrometry of a synthetic peptide, SKCGS, representing the actual tau sequence, identified the thiol as reacting with CA and ECox. Use of a cysteine double mutant of tau showed the necessity of cysteine for aggregation inhibition by CA. The interaction of CA with tau cysteines was reversible and the presence of CA did not impair the biological function of tau in tubulin assembly in vitro. Further, these compounds protected tau from oxidation caused by the reactive oxygen species, H2O2, and prevented subsequent formation of high molecular weight species that are considered to stimulate tangle formation. Finally, we observed that EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein. Our results suggest that small molecules that form a reversible interaction with cysteines have the potential to protect tau from abnormal modifications.

  20. Tau Acts as a Mediator for Alzheimer's Disease-Related Synaptic Deficits

    PubMed Central

    Liao, Dezhi; Miller, Eric C.; Teravskis, Peter J.

    2014-01-01

    The two histopathological hallmarks of Alzheimer's disease (AD) are amyloid plaques containing multiple forms of Aβ and neurofibrillary tangles containing phosphorylated tau proteins. As mild cognitive impairment frequently occurs long before the clinical diagnosis of Alzheimer's disease, the scientific community has been increasingly interested in the roles of Aβ and tau in earlier cellular changes that lead to functional deficits. Therefore, great progress has recently been made in understanding how Aβ or tau causes synaptic dysfunction. However, the interaction between the Aβ and tau-initiated intracellular cascades that lead to synaptic dysfunction remains elusive. The cornerstone of the two decade-old hypothetical amyloid cascade model is that amyloid pathologies precede tau pathologies. Although the premise of Aβ-tau pathway remains valid, the model keeps evolving as new signaling events are discovered that lead to functional deficits and neurodegeneration. Recent progress has been made in understanding Aβ-PrPC-Fyn-mediated neurotoxicity and synaptic deficits. Although still elusive, many novel upstream and downstream signaling molecules have been found to modulate tau mislocalization and tau hyperphosphorylation. Here we will discuss the mechanistic interactions between Aβ-PrPC-mediated neurotoxicity and tau-mediated synaptic deficits in an updated amyloid cascade model with calcium and tau as the central mediators. PMID:24712999

  1. Tau proteins: the molecular structure and mode of binding on microtubules

    PubMed Central

    1988-01-01

    Tau is a family of closely related proteins (55,000-62,000 mol wt) which are contained in the nerve cells and copolymerize with tubulin to induce the formation of microtubules in vitro. All information so far has indicated that tau is closely apposed to the microtubule lattice, and there was no indication of domains projecting from the microtubule polymer lattice. We have studied the molecular structure of the tau factor and its mode of binding on microtubules using the quick-freeze, deep-etch method (QF.DE) and low angle rotary shadowing technique. Phosphocellulose column-purified tubulin from porcine brain was polymerized with tau and the centrifuged pellets were processed by QF.DE. We observed periodic armlike elements (18.7 +/- 4.8 nm long) projecting from the microtubule surface. Most of the projections appeared to cross-link adjacent microtubules. We measured the longitudinal periodicity of tau projections on the microtubules and found it to match the 6-dimer pattern better than the 12-dimer pattern. The stoichiometry of tau versus tubulin in preparations of tau saturated microtubules was 1:approximately 5.0 (molar ratio). Tau molecules adsorbed on mica took on rodlike forms (56.1 +/- 14.1 nm long). Although both tau and MAP1 are contained in axons, competitive binding studies demonstrated that the binding sites of tau and MAP1A on the microtubule surfaces are most distinct, although they may partially overlap. PMID:3139677

  2. Autophagic degradation of tau in primary neurons and its enhancement by trehalose.

    PubMed

    Krüger, Ulrike; Wang, Yipeng; Kumar, Satish; Mandelkow, Eva-Maria

    2012-10-01

    Modulating the tau level may represent a therapeutic target for Alzheimer's disease (AD), as accumulating evidence shows that Abeta-induced neurodegeneration is mediated by tau. It is therefore important to understand the expression and degradation of tau in neurons. Recently we showed that overexpressed mutant tau and tau aggregates are degraded via the autophagic pathway in an N2a cell model. Here we investigated whether autophagy is involved in the degradation of endogenous tau in cultured primary neurons. We activated this pathway in primary neurons with trehalose, an enhancer of autophagy. This resulted in the reduction of endogenous tau protein. Tau phosphorylation at several sites elevated in AD pathology had little influence on its degradation by autophagy. Furthermore, by using a neuronal cell model of tauopathy, we showed that activation of autophagy suppresses tau aggregation and eliminates cytotoxicity. Notably, apart from activating autophagy, trehalose also inhibits tau aggregation directly. Thus, trehalose may be a good candidate for developing therapeutic strategies for AD and other tauopathies.

  3. Multiple mechanisms of extracellular tau spreading in a non-transgenic tauopathy model

    PubMed Central

    Le, Meghan N; Kim, Wonhee; Lee, Sangmook; McKee, Ann C; Hall, Garth F

    2012-01-01

    While the interneuronal propagation of neurofibrillary lesions in Alzheimer’s disease and other tauopathies now appears to involve the spreading of tau-associated toxicity, little is known about its mechanism. We characterized the movement of human tau through the brain of a non-transgenic lower vertebrate tauopathy model in which full-length wild type and mutant human tau isoforms were expressed in identified neurons, thus permitting the identification and localization of EC tau sources. We describe two distinct patterns of tau spreading that correspond to tau species that lack (MTBR-) and contain (MTBR+) the tau microtubule-binding region. These patterns illustrate the production, migration and uptake of EC tau and resemble some of the extracellular tau deposits typically seen in human brain after repeated traumatic injury in cases of chronic traumatic encephalopathy (CTE). We propose that misprocessed human tau can spread between CNS neurons via a variety of non-synaptic mechanisms as well as synaptically mediated mechanisms. PMID:23383401

  4. CSF tau markers are correlated with hippocampal volume in Alzheimer's disease.

    PubMed

    de Souza, Leonardo C; Chupin, Marie; Lamari, Foudil; Jardel, Claude; Leclercq, Delphine; Colliot, Olivier; Lehéricy, Stéphane; Dubois, Bruno; Sarazin, Marie

    2012-07-01

    Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimer's disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.

  5. Stages and Conformations of the Tau Repeat Domain during Aggregation and Its Effect on Neuronal Toxicity*

    PubMed Central

    Kumar, Satish; Tepper, Katharina; Kaniyappan, Senthilvelrajan; Biernat, Jacek; Wegmann, Susanne; Mandelkow, Eva-Maria; Müller, Daniel J.; Mandelkow, Eckhard

    2014-01-01

    Several neurodegenerative diseases are characterized by the aggregation and posttranslational modifications of Tau protein. Its “repeat domain” (TauRD) is mainly responsible for the aggregation properties, and oligomeric forms are thought to dominate the toxic effects of Tau. Here we investigated the conformational transitions of this domain during oligomerization and aggregation in different states of β-propensity and pseudo-phosphorylation, using several complementary imaging and spectroscopic methods. Although the repeat domain generally aggregates more readily than full-length Tau, its aggregation was greatly slowed down by phosphorylation or pseudo-phosphorylation at the KXGS motifs, concomitant with an extended phase of oligomerization. Analogous effects were observed with pro-aggregant variants of TauRD. Oligomers became most evident in the case of the pro-aggregant mutant TauRDΔK280, as monitored by atomic force microscopy, and the fluorescence lifetime of Alexa-labeled Tau (time-correlated single photon counting (TCSPC)), consistent with its pronounced toxicity in mouse models. In cell models or primary neurons, neither oligomers nor fibrils of TauRD or TauRDΔK280 had a toxic effect, as seen by assays with lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, respectively. However, oligomers of pro-aggregant TauRDΔK280 specifically caused a loss of spine density in differentiated neurons, indicating a locally restricted impairment of function. PMID:24825901

  6. The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation.

    PubMed

    Stieler, Jens T; Bullmann, Torsten; Kohl, Franziska; Tøien, Øivind; Brückner, Martina K; Härtig, Wolfgang; Barnes, Brian M; Arendt, Thomas

    2011-01-18

    Abnormal phosphorylation and aggregation of tau protein are hallmarks of a variety of neurological disorders, including Alzheimer's disease (AD). Increased tau phosphorylation is assumed to represent an early event in pathogenesis and a pivotal aspect for aggregation and formation of neurofibrillary tangles. However, the regulation of tau phosphorylation in vivo and the causes for its increased stage of phosphorylation in AD are still not well understood, a fact that is primarily based on the lack of adequate animal models. Recently we described the reversible formation of highly phosphorylated tau protein in hibernating European ground squirrels. Hence, mammalian hibernation represents a model system very well suited to study molecular mechanisms of both tau phosphorylation and dephosphorylation under in vivo physiological conditions. Here, we analysed the extent and kinetics of hibernation-state dependent tau phosphorylation in various brain regions of three species of hibernating mammals: arctic ground squirrels, Syrian hamsters and black bears. Overall, tau protein was highly phosphorylated in torpor states and phosphorylation levels decreased after arousal in all species. Differences between brain regions, hibernation-states and phosphosites were observed with respect to degree and kinetics of tau phosphorylation. Furthermore, we tested the phosphate net turnover of tau protein to analyse potential alterations in kinase and/or phosphatase activities during hibernation. Our results demonstrate that the hibernation-state dependent phosphorylation of tau protein is specifically regulated but involves, in addition, passive, temperature driven regulatory mechanisms. By determining the activity-state profile for key enzymes of tau phosphorylation we could identify kinases potentially involved in the differentially regulated, reversible tau phosphorylation that occurs during hibernation. We show that in black bears hibernation is associated with conformational

  7. A Novel, Ultrasensitive Assay for Tau: Potential for Assessing Traumatic Brain Injury in Tissues and Biofluids

    PubMed Central

    Chang, Binggong; Davies, Peter; Wagner, Amy K.; Robertson, Claudia S.; Wang, Kevin K.W.

    2015-01-01

    Abstract Traumatic brain injury (TBI) is a cause of death and disability and can lead to tauopathy-related dementia at an early age. Pathologically, TBI results in axonal injury that is coupled to tau hyperphosphorylation, leading to microtubule instability and tau-mediated neurodegeneration. This suggests that the forms of this protein might serve as neuroinjury-related biomarkers for diagnosis of injury severity and prognosis of the neurological damage prior to clinical expression. We initially determined whether we could detect tau in body fluids using a highly sensitive assay. We used a novel immunoassay, enhanced immunoassay using multi-arrayed fiberoptics (EIMAF) either alone or in combination with rolling circle amplification (a-EIMAF) for the detection of total (T) and phosphorylated (P) tau proteins from brains and biofluids (blood, CSF) of rodents following controlled cortical impact (CCI) and human patients post severe TBI (sTBI). This assay technology for tau is the most sensitive to date with a detection limit of approximately 100 ag/mL for either T-tau and P-tau. In the rodent models, T-tau and P-tau levels in brain and blood increased following CCI during the acute phase and remained high during the chronic phase (30 d). In human CSF samples, T-tau and P-tau increased during the sampling period (5–6 d). T-tau and P-tau in human serum rose during the acute phase and decreased during the chronic stage but was still detectable beyond six months post sTBI. Thus, EIMAF has the potential for assessing both the severity of the proximal injury and the prognosis using easily accessible samples. PMID:25177776

  8. Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation*

    PubMed Central

    Mirbaha, Hilda; Holmes, Brandon B.; Sanders, David W.; Bieschke, Jan; Diamond, Marc I.

    2015-01-01

    Tau amyloid assemblies propagate aggregation from the outside to the inside of a cell, which may mediate progression of the tauopathies. The critical size of Tau assemblies, or “seeds,” responsible for this activity is currently unknown, but this could be important for the design of effective therapies. We studied recombinant Tau repeat domain (RD) and Tau assemblies purified from Alzheimer disease (AD) brain composed largely of full-length Tau. Large RD fibrils were first sonicated to create a range of assembly sizes. We confirmed our ability to resolve stable assemblies ranging from n = 1 to >100 units of Tau using size exclusion chromatography, fluorescence correlation spectroscopy, cross-linking followed by Western blot, and mass spectrometry. All recombinant Tau assemblies bound heparan sulfate proteoglycans on the cell surface, which are required for Tau uptake and seeding, because they were equivalently sensitive to inhibition by heparin and chlorate. However, cells only internalized RD assemblies of n ≥ 3 units. We next analyzed Tau assemblies from AD or control brains. AD brains contained aggregated species, whereas normal brains had predominantly monomer, and no evidence of large assemblies. HEK293 cells and primary neurons spontaneously internalized Tau of n ≥ 3 units from AD brain in a heparin- and chlorate-sensitive manner. Only n ≥ 3-unit assemblies from AD brain spontaneously seeded intracellular Tau aggregation in HEK293 cells. These results indicate that a clear minimum size (n = 3) of Tau seed exists for spontaneous propagation of Tau aggregation from the outside to the inside of a cell, whereas many larger sizes of soluble aggregates trigger uptake and seeding. PMID:25887395

  9. Characterization of tryptic hydrolysis of alpha-lactalbumin/saponin mixture and structural change of alpha-lactalbumin interacting with soybean saponin.

    PubMed

    Shimoyamada, Makoto; Okada, Yuri; Watanabe, Kenji; Yamauchi, Ryo

    2005-03-15

    Bovine milk alpha-lactalbumin (alpha-La) was mixed with soybean saponin, and the resulting mixture was hydrolyzed by trypsin. Saponin increased the tryptic-hydrolysis level of alpha-La only at relatively high phosphate buffer concentrations (> or = 0.05 M). T(1) experiments with acetylated soybean saponin demonstrated that there were some interactions between alpha-La and saponin not only at high concentrations of phosphate buffers but even at low concentrations as well. Circular dichroism spectra of alpha-La showed that the tertiary structure of alpha-La was changed through interactions with saponin only at high buffer concentrations. Furthermore, by analyzing the tryptic peptides from an alpha-La/saponin mixture, hydrolyzing rates at all or some of K5, R10, and K16 of alpha-La were accelerated by saponin interactions. The increase in the tryptic hydrolysis of alpha-La by saponin addition was considered due to modification of the tertiary structure of alpha-La by saponin.

  10. Probing light pseudoscalar, axial vector states through {eta}{sub b}{yields}{tau}{sup +}{tau}{sup -}

    SciTech Connect

    Rashed, Ahmed; Duraisamy, Murugeswaran; Datta, Alakabha

    2010-09-01

    In this paper, we explore the decay {eta}{sub b}{yields}{tau}{sup +}{tau}{sup -} as a probe for a light pseudoscalar or a light axial vector state. We estimate the standard model branching ratio for this decay to be {approx}4x10{sup -9}. We show that considerably larger branching ratios, up to the present experimental limit of {approx}8%, are possible in models with a light pseudoscalar or a light axial vector state. As we do not include possible mixing effects between the light pseudoscalar and the {eta}{sub b}, our results should be reliable when the pseudoscalar mass is away from the {eta}{sub b} mass.

  11. Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX.

    PubMed

    Uchihara, Toshiki; Endo, Kentaro; Kondo, Hiromi; Okabayashi, Sachi; Shimozawa, Nobuhiro; Yasutomi, Yasuhiro; Adachi, Eijiro; Kimura, Nobuyuki

    2016-11-14

    Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7-36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30-34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20-25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms.

  12. Co-immunoprecipitation with Tau Isoform-specific Antibodies Reveals Distinct Protein Interactions and Highlights a Putative Role for 2N Tau in Disease*

    PubMed Central

    Liu, Chang; Song, Xiaomin; Nisbet, Rebecca

    2016-01-01

    Alternative splicing generates multiple isoforms of the microtubule-associated protein Tau, but little is known about their specific function. In the adult mouse brain, three Tau isoforms are expressed that contain either 0, 1, or 2 N-terminal inserts (0N, 1N, and 2N). We generated Tau isoform-specific antibodies and performed co-immunoprecipitations followed by tandem mass tag multiplexed quantitative mass spectrometry. We identified novel Tau-interacting proteins of which one-half comprised membrane-bound proteins, localized to the plasma membrane, mitochondria, and other organelles. Tau was also found to interact with proteins involved in presynaptic signal transduction. MetaCore analysis revealed one major Tau interaction cluster that contained 33 Tau pulldown proteins. To explore the pathways in which these proteins are involved, we conducted an ingenuity pathway analysis that revealed two significant overlapping pathways, “cell-to-cell signaling and interaction” and “neurological disease.” The functional enrichment tool DAVID showed that in particular the 2N Tau-interacting proteins were specifically associated with neurological disease. Finally, for a subset of Tau interactions (apolipoprotein A1 (apoA1), apoE, mitochondrial creatine kinase U-type, β-synuclein, synaptogyrin-3, synaptophysin, syntaxin 1B, synaptotagmin, and synapsin 1), we performed reverse co-immunoprecipitations, confirming the preferential interaction of specific isoforms. For example, apoA1 displayed a 5-fold preference for the interaction with 2N, whereas β-synuclein showed preference for 0N. Remarkably, a reverse immunoprecipitation with apoA1 detected only the 2N isoform. This highlights distinct protein interactions of the different Tau isoforms, suggesting that they execute different functions in brain tissue. PMID:26861879

  13. Tau binds to lipid membrane surfaces via short amphipathic helices located in its microtubule-binding repeats.

    PubMed

    Georgieva, Elka R; Xiao, Shifeng; Borbat, Peter P; Freed, Jack H; Eliezer, David

    2014-09-16

    Tau is a microtubule-associated protein that is genetically linked to dementia and linked to Alzheimer's disease via its presence in intraneuronal neurofibrillary tangle deposits, where it takes the form of aggregated paired helical and straight filaments. Although the precise mechanisms by which tau contributes to neurodegeneration remain unclear, tau aggregation is commonly considered to be a critical component of tau-mediated pathogenicity. Nevertheless, the context in which tau aggregation begins in vivo is unknown. Tau is enriched in membrane-rich neuronal structures such as axons and growth cones, and can interact with membranes both via intermediary proteins and directly via its microtubule-binding domain (MBD). Membranes efficiently facilitate tau aggregation in vitro, and may therefore provide a physiologically relevant context for nucleating tau aggregation in vivo. Furthermore, tau-membrane interactions may potentially play a role in tau's poorly understood normal physiological functions. Despite the potential importance of direct tau-membrane interactions for tau pathology and physiology, the structural mechanisms that underlie such interactions remain to be elucidated. Here, we employ electron spin resonance spectroscopy to investigate the secondary and long-range structural properties of the MBD of three-repeat tau isoforms when bound to lipid vesicles and membrane mimetics. We show that the membrane interactions of the tau MBD are mediated by short amphipathic helices formed within each of the MBD repeats in the membrane-bound state. To our knowledge, this is the first detailed elucidation of helical tau structure in the context of intact lipid bilayers. We further show, for the first time (to our knowledge), that these individual helical regions behave as independent membrane-binding sites linked by flexible connecting regions. These results represent the first (to our knowledge) detailed structural view of membrane-bound tau and provide insights

  14. Aluminum interaction with human brain tau protein phosphorylation by various kinases

    SciTech Connect

    El-Sebae; Abou Zeid, M.M.; Saleh, M.A. . Environmental Chemistry and Toxicology Lab.); Abdel-Ghany, M.E.; Shalloway, D. . Section of Biochemistry, Mol, and Cell Biology); Blancato, J. . Environmental Monit. Systems Lab.)

    1993-01-01

    Phosphorylation is an indispensable process for energy and signal transduction in biological systems. AlCl[sub 3] at 10 nM to 10 [mu]M range activated in-vitro [[gamma][sup [minus]32]P]ATP phosphorylation of the brain ([tau]) [Gamma] protein in both normal human or E.coli expressed [Gamma] forms; in the presence of the kinases P34,PKP, and PKC. However, higher concentrations of AlCl[sub 3] inhibited the [Gamma] phosphorylation with P34, PKP, and PKC to a maximum at 1 mM level. AlCl[sub 3] at 100 [mu]M to 500 [mu]M range induced non-enzymatic phosphorylation of [Gamma] with [gamma]-ATP, [gamma]-GTP, and [alpha]-GRP. AlCl[sub 3] activated histone phosphorylation by P34 in a similar pattern. The hyperphosphorylation of [Gamma] by Al[sup 3+] was accompanied in molecular shift and mobility retardation in SDS-PAGE. This may demonstrate the mechanism of the long term neurological effect of Al[sub 3+] in human brain leading to the formation of the neutrofibrillary tangles related to Alzeheimer's disease.

  15. Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency.

    PubMed

    Suzuki, Y J; Tsuchiya, M; Wassall, S R; Choo, Y M; Govil, G; Kagan, V E; Packer, L

    1993-10-12

    d-alpha-Tocopherol and d-alpha-tocotrienol are two vitamin E constituents having the same aromatic chromanol "head" but different hydrocarbon "tails". alpha-Tocotrienol has been shown to be more potent in protecting against free radical-induced oxidative stress than alpha-tocopherol. Simple models of phospholipid membrane systems were used to investigate the mechanism of the antioxidant potency of alpha-tocotrienol in terms of its effects on membrane order and reorientation dynamics. Chemiluminescence and fluorescence measurements demonstrated that alpha-tocotrienol exhibits significantly greater peroxyl radical scavenging potency than alpha-tocopherol in phosphatidylcholine liposomes, whereas both antioxidants have identical activity in hexane. This suggests that the antioxidant potency of alpha-tocotrienol requires the membrane environment. When alpha-tocopherol and alpha-tocotrienol were examined for their effects on phospholipid molecular order using conventional ESR spin labeling with 5- and 16-position-labeled doxylstearic acid, although both vitamin E constituents disordered the gel phase and stabilized the liquid-crystalline phase, no differences were observed between the effects of the two compounds. A slightly greater increase (19% vs 15%) in ordering of the liquid-crystalline state due to alpha-tocopherol, however, was discerned in noninvasive 2H NMR experiments. The difference is most noticeable near C10-C13 positions of the phospholipid chain, possibly suggesting alpha-tocotrienol is located closer to the membrane surface. Saturation-transfer ESR, furthermore, revealed that on the time scale tau c = 10(-7)-10(-3) s the rates of rotation about the long molecular axis and of the wobbling motion of the axis are modified to differing extents by the two forms of the vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction

    PubMed Central

    Mietelska-Porowska, Anna; Wasik, Urszula; Goras, Marcelina; Filipek, Anna; Niewiadomska, Grazyna

    2014-01-01

    Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons. PMID:24646911

  17. The Metamorphic Nature of the Tau Protein: Dynamic Flexibility Comes at a Cost

    PubMed Central

    Sabbagh, Jonathan J.; Dickey, Chad A.

    2016-01-01

    Accumulation of the microtubule associated protein tau occurs in several neurodegenerative diseases including Alzheimer's disease (AD). The tau protein is intrinsically disordered, giving it unique structural properties that can be dynamically altered by post-translational modifications such as phosphorylation and cleavage. Over the last decade, technological advances in nuclear magnetic resonance (NMR) spectroscopy and structural modeling have permitted more in-depth insights into the nature of tau. These studies have helped elucidate how metamorphism of tau makes it ideally suited for dynamic microtubule regulation, but how it also facilitates tau self-assembly, oligomerization, and neurotoxicity. This review will focus on how the distinct structure of tau governs its function, accumulation, and toxicity as well as how other cellular factors such as molecular chaperones control these processes. PMID:26834532

  18. The Metamorphic Nature of the Tau Protein: Dynamic Flexibility Comes at a Cost.

    PubMed

    Sabbagh, Jonathan J; Dickey, Chad A

    2016-01-01

    Accumulation of the microtubule associated protein tau occurs in several neurodegenerative diseases including Alzheimer's disease (AD). The tau protein is intrinsically disordered, giving it unique structural properties that can be dynamically altered by post-translational modifications such as phosphorylation and cleavage. Over the last decade, technological advances in nuclear magnetic resonance (NMR) spectroscopy and structural modeling have permitted more in-depth insights into the nature of tau. These studies have helped elucidate how metamorphism of tau makes it ideally suited for dynamic microtubule regulation, but how it also facilitates tau self-assembly, oligomerization, and neurotoxicity. This review will focus on how the distinct structure of tau governs its function, accumulation, and toxicity as well as how other cellular factors such as molecular chaperones control these processes.

  19. Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau.

    PubMed

    Siddiqua, Ayisha; Luo, Yin; Meyer, Virginia; Swanson, Michael A; Yu, Xiang; Wei, Guanghong; Zheng, Jie; Eaton, Gareth R; Ma, Buyong; Nussinov, Ruth; Eaton, Sandra S; Margittai, Martin

    2012-06-20

    Tau pathology in Alzheimer's disease is intimately linked to the deposition of proteinacious filaments, which akin to infectious prions, have been proposed to spread via seeded conversion. Here we use double electron-electron resonance (DEER) spectroscopy in combination with extensive computational analysis to show that filaments of three- (3R) and four-repeat (4R) tau are conformationally distinct. Distance measurements between spin labels in the third repeat, reveal tau amyloid filaments as ensembles of known β-strand-turn-β-strand U-turn motifs. Whereas filaments seeded with 3R tau are structurally homogeneous, filaments seeded with 4R tau are heterogeneous, composed of at least three distinct conformers. These findings establish a molecular basis for the seeding barrier between different tau isoforms and offer a new powerful approach for investigating the composition and dynamics of amyloid fibril ensembles.

  20. The Ambiguous Relationship of Oxidative Stress, Tau Hyperphosphorylation, and Autophagy Dysfunction in Alzheimer's Disease

    PubMed Central

    Liu, Zhenzhen; Li, Tao; Li, Ping; Wei, Nannan; Zhao, Zhiquan; Liang, Huimin; Ji, Xinying; Chen, Wenwu; Xue, Mengzhou; Wei, Jianshe

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβ plaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD. PMID:26171115

  1. Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease.

    PubMed

    Wang, Jun; Santa-Maria, Ismael; Ho, Lap; Ksiezak-Reding, Hanna; Ono, Kenjiro; Teplow, David B; Pasinetti, Giulio Maria

    2010-01-01

    Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain.

  2. Recent Results on Charm and Tau Physics from BaBar And Belle

    SciTech Connect

    Salvatore, Fabrizio F.; /Royal Holloway, U. of London

    2007-10-15

    Recent results on charm and tau physics obtained at the BABAR and Belle experiments are presented in this article. The charm section will be focused on the most recent results on D{sup 0}{bar D}{sup 0} mixing at Belle and on the measurement of the pseudoscalar decay constant f{sub Ds} using charm tagged e+e- events at BABAR. In the tau section the recent results on Lepton Flavor Violation from tau decays will be discussed, as well as the recent result on the rare decay {tau}{sup -} {yields} 3{pi}{sup -}2{pi}{sup +}2{pi}{sup 0}{nu}{sub {tau}} at BABAR and the measurement of the {tau} lepton mass at Belle.

  3. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain

    PubMed Central

    Takeda, Shuko; Wegmann, Susanne; Cho, Hansang; DeVos, Sarah L.; Commins, Caitlin; Roe, Allyson D.; Nicholls, Samantha B.; Carlson, George A.; Pitstick, Rose; Nobuhara, Chloe K.; Costantino, Isabel; Frosch, Matthew P.; Müller, Daniel J.; Irimia, Daniel; Hyman, Bradley T.

    2015-01-01

    Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development. PMID:26458742

  4. Report on key comparison COOMET.AUV.A-K5: pressure calibration of laboratory standard microphones in the frequency range 2 Hz to 10 kHz

    NASA Astrophysics Data System (ADS)

    Dobrowolska, D.; Kosterov, A.

    2016-01-01

    This is the final report for regional key comparison COOMET.AUV.A-K5 on the pressure calibration of laboratory standard microphones in the frequency range from 2 Hz to 10 kHz. Two laboratories—Central Office of Measures (GUM)—the national metrology institute for Poland and the State Enterprise Scientific-Research Institute for Metrology of Measurement and Control Systems (DP NDI Systema)— the designated institute for acoustics in Ukraine took part in this comparison with the GUM as a pilot. One travelling type LS1P microphone was circulated to the participants and results in the form of regular calibration certificates were collected. The results of the DP NDI Systema obtained in this comparison were linked to the CCAUV.A-K5 key comparison through the joint participation of the GUM. The degrees of equivalence were computed for DP NDI Systema with respect to the CCAUV.A-K5 key comparison reference value. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCAUV, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  5. Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein.

    PubMed

    Smith, Lynnae M; Coffey, Mary P; Klaver, Andrea C; Loeffler, David A

    2013-08-01

    Intravenous immunoglobulin (IVIG) products are prepared from plasma immunoglobulins from healthy donors. Pilot studies suggest that IVIG may stabilize cognitive functioning in patients with mild-to-moderate Alzheimer's disease. This study measured antibodies to recombinant human tau protein in the IVIG products Gammagard (Baxter), Gamunex (Talecris), and Flebogamma (Grifols). Anti-tau antibodies were measured by ELISA, subtracting IVIG's polyvalent binding from its binding to tau-coated wells to calculate specific anti-tau antibody levels. Because polyvalent binding of IVIG products may interfere with ELISA measurement of their specific antibody levels, the percentage of binding of each IVIG product to tau-coated wells that was specific for tau was also determined. Specific anti-tau antibodies were detected in all three IVIG products, with significant differences between these products (p<0.001) even when Flebogamma's anti-tau antibodies were doubled to account for its preparation as a 5% solution vs. 10% solutions for Gammagard and Gamunex (means: Gammagard, 3.1 μg/ml; Gamunex, 2.5 μg/ml; Flebogamma, 1.2 μg/ml). The percentages of each IVIG product's specific binding to tau-coated wells also varied between the various products (p<0.001) and between all pairs of IVIG products (means: Gammagard, 73.1%; Flebogamma, 54.5%; Gamunex, 37.4%; p<0.01 for all pairwise comparisons). These findings indicate that IVIG products contain specific anti-tau antibodies. The concentrations of these antibodies and the percentages of specific binding of IVIG to tau-coated wells vary between IVIG products. Further studies are indicated to determine if IVIG also contains antibodies to pathologic forms of tau.

  6. Orbit and Stellar Properties of the Young Triple V807 Tau

    DTIC Science & Technology

    2012-09-10

    spectral step (∼250 K) and calculating the range of variation in the derived parameters . We know from the FGS photometry that V807 Tau A is variable... parameters – stars: individual (V807 Tau) – stars: pre-main sequence Online-only material: color figures 1. INTRODUCTION V807 Tau (Elias 12, HBC 404) is a...convert the flux ratios to component magnitudes by using published photometry obtained for the unresolved system. The top portion of the table lists the

  7. Development of in vivo Biomarkers for Progressive Tau Pathology after Traumatic Brain Injury

    DTIC Science & Technology

    2014-02-01

    an ongoing degenerative process similar to other diseases characterized by progressive tau pathology such as Alzheimer disease and frontotemporal...dementia. A leading hypothesis regarding the progression of tau pathology in Alzheimer disease and frontotemporal dementia is that tau aggregates formed...post/Entrez/query?db=m&form=6&dopt=r&uid=11484824. 19. Geddes JF, Vowles GH, Robinson SF, Sutcliffe JC. Neurofibrillary tangles, but not Alzheimer

  8. Supersymmetric R parity violation and CP asymmetry in semileptonic {tau} decays

    SciTech Connect

    Delepine, D.; Faisel, G.; Khalil, S.

    2008-01-01

    We analyze the CP violation in the semileptonic |{delta}S|=1 {tau} decays in supersymmetric extensions of the standard model with R parity violating term. We show that the CP asymmetry of {tau} decay is enhanced significantly and the current experimental limits obtained by CLEO collaborations can be easily accommodated. We argue that observing CP violation in semileptonic {tau} decay would be a clear evidence for R parity violating supersymmetry extension of the standard model.

  9. Conformational features of tau fibrils from Alzheimer’s disease brain are faithfully propagated by unmodified recombinant protein

    PubMed Central

    Morozova, Olga A.; March, Zachary M.; Robinson, Anne S.; Colby, David W.

    2014-01-01

    Fibrils composed of tau protein are a pathological hallmark of several neurodegenerative disorders including Alzheimer’s disease (AD). Here we show that when recombinant tau protein is seeded with paired helical filaments (PHFs) isolated from AD brain, the amyloid formed shares many of the structural features of AD PHFs. In contrast, tau amyloids formed with heparin as an inducing agent—a common biochemical model of tau misfolding—are structurally distinct from brain-derived PHFs. Using ultrastructural analysis by electron microscopy, circular dichroism, and chemical denaturation, we found that AD seeded recombinant tau fibrils were not significantly different than tau fibrils isolated from AD brain tissue. Tau fibrils produced by incubating recombinant tau with heparin had significantly narrower fibrils with a longer periodicity, higher chemical stability, and distinct secondary structure compared to AD PHFs. The addition of heparin to the reaction of recombinant tau and AD PHFs also corrupted the templating process, resulting in a mixture of fibril conformations. Our results suggest that AD-isolated PHFs act as a conformational template for the formation of recombinant tau fibrils. Therefore, the use of AD PHFs as seeds to stimulate recombinant tau amyloid formation produces synthetic tau fibers that that closely resemble those associated with AD pathology and provides a biochemical model of tau misfolding that may be of improved utility for structural studies and drug screening. These results also demonstrate that posttranslational modifications such as phosphorylation are not a prerequisite for the propagation of the tau fibril conformation found in AD. PMID:24033133

  10. Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease.

    PubMed

    Platt, T L; Beckett, T L; Kohler, K; Niedowicz, D M; Murphy, M P

    2016-02-19

    Obesity and type 2 diabetes mellitus (T2DM) convey an increased risk for developing dementia. The microtubule-associated protein tau is implicated in neurodegenerative disease by undergoing hyperphosphorylation and aggregation, leading to cytotoxicity and neurodegeneration. Enzymes involved in the regulation of tau phosphorylation, such as GSK3β, are tightly associated with pathways found to be dysregulated in T2DM. We have shown previously that leptin-resistant mice, which develop obesity and a diabetic phenotype, display elevated levels of tau phosphorylation. Here we show cells cultured with leptin, an adipokine shown to have neuroprotective effects, reduces tau phosphorylation. To explore how this mechanism works in vivo we transduced an existing diabetic mouse line (Lepr(db/db)) with a tau mutant (tau(P301L)) via adeno-associated virus (AAV). The resulting phenotype included a striking increase in tau phosphorylation and the number of neurofibrillary tangles (NFTs) found within the hippocampus. We conclude that leptin resistance-induced obesity and diabetes accelerates the development of tau pathology. This model of metabolic dysfunction and tauopathy provides a new system in which to explore the mechanisms underlying the ways in which leptin resistance and diabetes influence development of tau pathology, and may ultimately be related to the development of NFTs.

  11. Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid

    PubMed Central

    King, Michelle E.; Kan, Ho-Man; Baas, Peter W.; Erisir, Alev; Glabe, Charles G.; Bloom, George S.

    2006-01-01

    Alzheimer's Disease (AD) is defined histopathologically by extracellular β-amyloid (Aβ) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which Aβ lies upstream of tau, but the steps that connect Aβ to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular Aβ in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar Aβ42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar Aβ40, and microtubules were insensitive to fibrillar Aβ. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible Aβ. PMID:17101697

  12. Search for Lepton Flavor Violation in the Decay tau -> electron gamma

    SciTech Connect

    Aubert, B.; Barate, R.; Boutigny, D.; Couderc, F.; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Tisserand, V.; Zghiche, A.; Grauges, E.; Palano, A.; Pappagallo, M.; Pompili, A.; Chen, J.C.; Qi, N.D.; Rong, G.; Wang, P.; Zhu, Y.S.; Eigen, G.; Ofte, I.; Stugu, B. /Bergen U. /LBL, Berkeley /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /Bristol U. /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UCLA /UC, Riverside /UC, San Diego /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /Ferrara U. /INFN, Ferrara /Frascati /Genoa U. /INFN, Genoa /Harvard U. /Heidelberg U. /Karlsruhe U., EKP /Imperial Coll., London /Iowa U. /Iowa State U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT, LNS /McGill U. /Milan U. /INFN, Milan /Mississippi U. /Montreal U. /Mt. Holyoke Coll. /Naples U. /INFN, Naples /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /Padua U. /INFN, Padua /Paris U., VI-VII /Pennsylvania U. /Perugia U. /INFN, Perugia /Pisa U. /INFN, Pisa /Prairie View A-M /Princeton U. /Rome U. /INFN, Rome /Rostock U. /Rutherford /DAPNIA, Saclay /South Carolina U. /SLAC /Stanford U., Phys. Dept. /SUNY, Stony Brook /Tennessee U. /Texas U. /Texas U., Dallas /Turin U. /INFN, Turin /Trieste U. /INFN, Trieste /Valencia U., IFIC /Vanderbilt U. /Victoria U. /Warwick U. /Wisconsin U., Madison /Yale U. /Basilicata U., Potenza

    2005-08-26

    A search for the non-conservation of lepton flavor in the decay {tau}{sup {+-}} {yields} e{sup {+-}}{gamma} has been performed with 2.07 x 10{sup 8} e{sup +}e{sup -} {yields} {tau}{sup +}{tau}{sup -} events collected by the BABAR detector at the PEP-II storage ring at a center-of-mass energy near 10.58 GeV. They find no evidence for a signal and set an upper limit on the branching ratio of {Beta}({tau}{sup {+-}} {yields} e{sup {+-}}{gamma}) < 1.1 x 10{sup -7} at 90% confidence level.

  13. The novel Tau mutation G335S: clinical, neuropathological and molecular characterization.

    PubMed

    Spina, Salvatore; Murrell, Jill R; Yoshida, Hirotaka; Ghetti, Bernardino; Bermingham, Niamh; Sweeney, Brian; Dlouhy, Stephen R; Crowther, R Anthony; Goedert, Michel; Keohane, Catherine

    2007-04-01

    Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.

  14. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease.

    PubMed

    Brier, Matthew R; Gordon, Brian; Friedrichsen, Karl; McCarthy, John; Stern, Ari; Christensen, Jon; Owen, Christopher; Aldea, Patricia; Su, Yi; Hassenstab, Jason; Cairns, Nigel J; Holtzman, David M; Fagan, Anne M; Morris, John C; Benzinger, Tammie L S; Ances, Beau M

    2016-05-11

    Alzheimer's disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD.

  15. Internalized Tau sensitizes cells to stress by promoting formation and stability of stress granules

    PubMed Central

    Brunello, Cecilia A.; Yan, Xu; Huttunen, Henri J.

    2016-01-01

    Stress granules are membrane-less RNA- and RNA-binding protein-containing complexes that are transiently assembled in stressful conditions to promote cell survival. Several stress granule-associated RNA-binding proteins have been associated with neurodegenerative diseases. In addition, a close link was recently identified between the stress granule core-nucleating protein TIA-1 and Tau. Tau is a central pathological protein in Alzheimer’s disease and other tauopathies, and misfolded, aggregated Tau is capable of propagating pathology via cell-to-cell transmission. Here we show that following internalization hyperphosphorylated extracellular Tau associates with stress granules in a TIA-1 dependent manner. Cytosolic Tau normally only weakly interacts with TIA-1 but mutations mimicking abnormal phosphorylation promote this interaction. We show that internalized Tau significantly delays normal clearance of stress granules in the recipient cells sensitizing them to secondary stress. These results suggest that secreted Tau species may have properties, likely related to its hyperphosphorylation and oligomerization, which promote pathological association of internalized Tau with stress granules altering their dynamics and reducing cell viability. We suggest that stress granules and TIA-1 play a central role in the cell-to-cell transmission of Tau pathology. PMID:27460788

  16. Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging

    PubMed Central

    2013-01-01

    Background Complex species-specific, developmental- and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e.g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease. Results Gene-targeting was used to delete exon 10 in murine tau on both alleles (E10−/−) to study its functional role. Moreover, mice devoid of exon 10 (E10+/−) on one allele were generated to investigate the effects of 1:1 balanced expression of 4R-/3R-tau protein, since equal amounts of 4R-/3R-tau protein are synthesized in human brain. Middle-aged E10−/− mice displayed sensorimotor disturbances in the rotarod when compared to age-matched E10+/− and wild-type mice, and their muscular grip strength was less than that of E10+/− mice. The performance of E10+/− mice and wild-type mice (E10+/+) was similar in sensorimotor tests. Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found. Conclusion Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging. Presumably related microtubule-stabilizing genes rescue other functions. PMID:24261309

  17. Search for lepton flavor violation in the decay tau+/- --> mu+ gamma.

    PubMed

    Aubert, B; Barate, R; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges-Pous, E; Palano, A; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Borgland, A W; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Fritsch, M; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Chevalier, N; Cottingham, W N; Kelly, M P; Latham, T E; Wilson, F F; Cuhadar-Donszelmann, T; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Thiessen, D; Khan, A; Kyberd, P; Teodorescu, L; Blinov, A E; Blinov, V E; Druzhinin, V P; Golubev, V B; Ivanchenko, V N; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bruinsma, M; Chao, M; Eschrich, I; Kirkby, D; Lankford, A J; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Weinstein, A J R; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Del Re, D; Hadavand, H K; Hill, E J; MacFarlane, D B; Paar, H P; Rahatlou, Sh; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Lu, A; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Yang, S; Jayatilleke, S; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P; Chen, S; Ford, W T; Nauenberg, U; Olivas, A; Rankin, P; Ruddick, W O; Smith, J G; Ulmer, K A; Zhang, J; Zhang, L; Chen, A; Eckhart, E A; Harton, J L; Soffer, A; Toki, W H; Wilson, R J; Zeng, Q; Spaan, B; Altenburg, D; Brandt, T; Brose, J; Dickopp, M; Feltresi, E; Hauke, A; Lacker, H M; Maly, E; Nogowski, R; Otto, S; Petzold, A; Schott, G; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Bernard, D; Bonneaud, G R; Grenier, P; Schrenk, S; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Bard, D J; Clark, P J; Muheim, F; Playfer, S; Xie, Y; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Sarti, A; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Patteri, P; Peruzzi, I M; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Crosetti, G; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Bailey, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Won, E; Dubitzky, R S; Langenegger, U; Marks, J; Uwer, U; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Gaillard, J R; Morton, G W; Nash, J A; Nikolich, M B; Taylor, G P; Charles, M J; Grenier, G J; Mallik, U; Mohapatra, A K; Cochran, J; Crawley, H B; Lamsa, J; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Yi, J; Arnaud, N; Davier, M; Giroux, X; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Petersen, T C; Pierini, M; Plaszczynski, S; Schune, M H; Wormser, G; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Chavez, C A; Coleman, J P; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Parry, R J; Payne, D J; Touramanis, C; Cormack, C M; Di Lodovico, F; Brown, C L; Cowan, G; Flack, R L; Flaecher, H U; Green, M G; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Winter, M A; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Hodgkinson, M C; Lafferty, G D; Naisbit, M T; Williams, J C; Chen, C; Farbin, A; Hulsbergen, W D; Jawahery, A; Kovalskyi, D; Lae, C K; Lillard, V; Roberts, D A; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Kofler, R; Koptchev, V B; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Taylor, F; Yamamoto, R K; Patel, P M; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Taras, P; Nicholson, H; Cavallo, N; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Wilden, L; Jessop, C P; LoSecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Lu, M; Potter, C T; Sinev, N B; Strom, D; Torrence, E; Colecchia, F; Dorigo, A; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; John, M J J; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Biasini, M; Covarelli, R; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bondioli, M; Bucci, F; Calderini, G; Carpinelli, M; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Morganti, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Simi, G; Walsh, J; Haire, M; Judd, D; Paick, K; Wagoner, D E; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Miftakov, V; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Tehrani, F Safai; Voena, C; Christ, S; Schröder, H; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Gopal, G P; Olaiya, E O; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Giraud, P-F; Graziani, G; de Monchenault, G Hamel; Kozanecki, W; Legendre, M; London, G W; Mayer, B; Vasseur, G; Yèche, Ch; Zito, M; Purohit, M V; Weidemann, A W; Wilson, J R; Yumiceva, F X; Abe, T; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Claus, R; Convery, M R; Cristinziani, M; De Nardo, G; Dingfelder, J C; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Fan, S; Field, R C; Glanzman, T; Gowdy, S J; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Soha, A; Stelzer, J; Strube, J; Su, D; Sullivan, M K; Va'vra, J; Wagner, S R; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Ahmed, M; Ahmed, S; Alam, M S; Ernst, J A; Saeed, M A; Saleem, M; Wappler, F R; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Kim, H; Ritchie, J L; Satpathy, A; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Poropat, P; Vitale, L; Vuagnin, G; Martinez-Vidal, F; Panvini, R S; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Jackson, P D; Kowalewski, R; Roney, J M; Sobie, R J; Yun, Z; Back, J J; Harrison, P F; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Graham, M; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mihalyi, A; Pan, Y; Prepost, R; Tan, P; von Wimmersperg-Toeller, J H; Wu, J; Wu, S L; Yu, Z; Greene, M G; Neal, H

    2005-07-22

    A search for the nonconservation of lepton flavor number in the decay tau(+/-) --> mu(+/-) has been performed using 2.07 x 10(8) e(+ )e(-) tau(+) tau(-) events produced at a center-of-mass energy near 10.58 GeV with the BABAR detector at the PEP-II storage ring. We find no evidence for a signal and set an upper limit on the branching ratio of Beta(tau(+/-) --> mu(+/-) gamma) < 6.8 x 10(-8) at 90% confidence level.

  18. Search for lepton flavor violation in the decay tau+/--->e+/-gamma.

    PubMed

    Aubert, B; Barate, R; Boutigny, D; Couderc, F; Karyotakis, Y; Lees, J P; Poireau, V; Tisserand, V; Zghiche, A; Grauges, E; Palano, A; Pappagallo, M; Pompili, A; Chen, J C; Qi, N D; Rong, G; Wang, P; Zhu, Y S; Eigen, G; Ofte, I; Stugu, B; Abrams, G S; Battaglia, M; Breon, A B; Brown, D N; Button-Shafer, J; Cahn, R N; Charles, E; Day, C T; Gill, M S; Gritsan, A V; Groysman, Y; Jacobsen, R G; Kadel, R W; Kadyk, J; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lynch, G; Mir, L M; Oddone, P J; Orimoto, T J; Pripstein, M; Roe, N A; Ronan, M T; Wenzel, W A; Barrett, M; Ford, K E; Harrison, T J; Hart, A J; Hawkes, C M; Morgan, S E; Watson, A T; Fritsch, M; Goetzen, K; Held, T; Koch, H; Lewandowski, B; Pelizaeus, M; Peters, K; Schroeder, T; Steinke, M; Boyd, J T; Burke, J P; Chevalier, N; Cottingham, W N; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Knecht, N S; Mattison, T S; McKenna, J A; Khan, A; Kyberd, P; Saleem, M; Teodorescu, L; Blinov, A E; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Kravchenko, E A; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Yushkov, A N; Best, D; Bondioli, M; Bruinsma, M; Chao, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Mommsen, R K; Roethel, W; Stoker, D P; Buchanan, C; Hartfiel, B L; Weinstein, A J R; Foulkes, S D; Gary, J W; Long, O; Shen, B C; Wang, K; Zhang, L; del Re, D; Hadavand, H K; Hill, E J; Macfarlane, D B; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Mazur, M A; Richman, J D; Verkerke, W; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Nesom, G; Schalk, T; Schumm, B A; Seiden, A; Spradlin, P; Williams, D C; Wilson, M G; Albert, J; Chen, E; Dubois-Felsmann, G P; Dvoretskii, A; Hitlin, D G; Minamora, J S; Narsky, I; Piatenko, T; Porter, F C; Ryd, A; Samuel, A; Andreassen, R; Mancinelli, G; Meadows, B T; Sokoloff, M D; Blanc, F; Bloom, P; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nauenberg, U; Olivas, A; Ruddick, W O; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Chen, A; Eckhart, E A; Soffer, A; Toki, W H; Wilson, R J; Zeng, Q; Altenburg, D; Feltresi, E; Hauke, A; Spaan, B; Brandt, T; Brose, J; Dickopp, M; Klose, V; Lacker, H M; Nogowski, R; Otto, S; Petzold, A; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Bernard, D; Bonneaud, G R; Grenier, P; Schrenk, S; Thiebaux, Ch; Vasileiadis, G; Verderi, M; Bard, D J; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Xie, Y; Andreotti, M; Azzolini, V; Bettoni, D; Bozzi, C; Calabrese, R; Cibinetto, G; Luppi, E; Negrini, M; Piemontese, L; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Patteri, P; Peruzzi, I M; Piccolo, M; Zallo, A; Buzzo, A; Capra, R; Contri, R; Lo Vetere, M; Macri, M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Brandenburg, G; Chaisanguanthum, K S; Morii, M; Won, E; Wu, J; Dubitzky, R S; Langenegger, U; Marks, J; Schenk, S; Uwer, U; Schott, G; Bhimji, W; Bowerman, D A; Dauncey, P D; Egede, U; Flack, R L; Gaillard, J R; Nash, J A; Nikolich, M B; Vazquez, W Panduro; Chai, X; Charles, M J; Mader, W F; Mallik, U; Mohapatra, A K; Ziegler, V; Cochran, J; Crawley, H B; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Yi, J; Arnaud, N; Davier, M; Giroux, X; Grosdidier, G; Höcker, A; Le Diberder, F; Lepeltier, V; Lutz, A M; Oyanguren, A; Petersen, T C; Plaszczynski, S; Rodier, S; Roudeau, P; Schune, M H; Stocchi, A; Wormser, G; Cheng, C H; Lange, D J; Simani, M C; Wright, D M; Bevan, A J; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; George, K A; Hutchcroft, D E; Parry, R J; Payne, D J; Schofield, K C; Touramanis, C; Cormack, C M; Di Lodovico, F; Menges, W; Sacco, R; Brown, C L; Cowan, G; Flaecher, H U; Green, M G; Hopkins, D A; Jackson, P S; McMahon, T R; Ricciardi, S; Salvatore, F; Brown, D; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Edgar, C L; Hodgkinson, M C; Kelly, M P; Lafferty, G D; Naisbit, M T; Williams, J C; Chen, C; Hulsbergen, W D; Jawahery, A; Kovalskyi, D; Lae, C K; Roberts, D A; Simi, G; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Kofler, R; Koptchev, V B; Li, X; Moore, T B; Saremi, S; Staengle, H; Willocq, S; Cowan, R; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Kim, H; Patel, P M; Robertson, S H; Lazzaro, A; Lombardo, V; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Reidy, J; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Taras, P; Viaud, B; Nicholson, H; Cavallo, N; De Nardo, G; Fabozzi, F; Gatto, C; Lista, L; Monorchio, D; Paolucci, P; Piccolo, D; Sciacca, C; Baak, M; Bulten, H; Raven, G; Snoek, H L; Wilden, L; Jessop, C P; Losecco, J M; Allmendinger, T; Benelli, G; Gan, K K; Honscheid, K; Hufnagel, D; Jackson, P D; Kagan, H; Kass, R; Pulliam, T; Rahimi, A M; Ter-Antonyan, R; Wong, Q K; Brau, J; Frey, R; Igonkina, O; Lu, M; Potter, C T; Sinev, N B; Strom, D; Strube, J; Torrence, E; Galeazzi, F; Margoni, M; Morandin, M; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Benayoun, M; Briand, H; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; John, M J J; Leruste, Ph; Malclès, J; Ocariz, J; Roos, L; Therin, G; Behera, P K; Gladney, L; Guo, Q H; Panetta, J; Biasini, M; Covarelli, R; Pacetti, S; Pioppi, M; Angelini, C; Batignani, G; Bettarini, S; Bucci, F; Calderini, G; Carpinelli, M; Cenci, R; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Morganti, M; Neri, N; Paoloni, E; Rama, M; Rizzo, G; Walsh, J; Haire, M; Judd, D; Wagoner, D E; Biesiada, J; Danielson, N; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Bellini, F; Cavoto, G; D'Orazio, A; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Safai Tehrani, F; Voena, C; Schröder, H; Wagner, G; Waldi, R; Adye, T; De Groot, N; Franek, B; Gopal, G P; Olaiya, E O; Wilson, F F; Aleksan, R; Emery, S; Gaidot, A; Ganzhur, S F; Graziani, G; Hamel de Monchenault, G; Kozanecki, W; Legendre, M; London, G W; Mayer, B; Vasseur, G; Yèche, Ch; Zito, M; Purohit, M V; Weidemann, A W; Wilson, J R; Yumiceva, F X; Abe, T; Allen, M T; Aston, D; Bartoldus, R; Berger, N; Boyarski, A M; Buchmueller, O L; Claus, R; Coleman, J P; Convery, M R; Cristinziani, M; Dingfelder, J C; Dong, D; Dorfan, J; Dujmic, D; Dunwoodie, W; Fan, S; Field, R C; Glanzman, T; Gowdy, S J; Hadig, T; Halyo, V; Hast, C; Hryn'ova, T; Innes, W R; Kelsey, M H; Kim, P; Kocian, M L; Leith, D W G S; Libby, J; Luitz, S; Luth, V; Lynch, H L; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ozcan, V E; Perazzo, A; Perl, M; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Roat, C; Ahmed, M; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Saeed, M A; Wappler, F R; Zain, S B; Bugg, W; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Satpathy, A; Schwitters, R F; Izen, J M; Kitayama, I; Lou, X C; Ye, S; Bianchi, F; Bona, M; Gallo, F; Gamba, D; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Dittongo, S; Grancagnolo, S; Lanceri, L; Vitale, L; Martinez-Vidal, F; Panvini, R S; Banerjee, Sw; Bhuyan, B; Brown, C M; Fortin, D; Hamano, K; Kowalewski, R; Roney, J M; Sobie, R J; Back, J J; Harrison, P F; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Cheng, B; Dasu, S; Datta, M; Eichenbaum, A M; Flood, K T; Graham, M; Hollar, J J; Johnson, J R; Kutter, P E; Li, H; Liu, R; Mellado, B; Mihalyi, A; Pan, Y; Pierini, M; Prepost, R; Tan, P; Wu, S L; Yu, Z; Neal, H

    2006-02-03

    A search for the nonconservation of lepton flavor in the decay tau+/--->e+/-gamma has been performed with 2.07x10(8) e+e--->tau+tau- events collected by the BABAR detector at the SLAC PEP II storage ring at a center-of-mass energy near 10.58 GeV. We find no evidence for a signal and set an upper limit on the branching ratio of Beta(tau+/--->e+/-gamma)<1.1x10(-7) at 90% confidence level.

  19. Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation

    PubMed Central

    Sun, Xu-Ying; Tuo, Qing-Zhang; Liuyang, Zhen-Yu; Xie, Ao-Ji; Feng, Xiao-Long; Yan, Xiong; Qiu, Mei; Li, Shen; Wang, Xiu-Lian; Cao, Fu-Yuan; Wang, Xiao-Chuan; Wang, Jian-Zhi; Liu, Rong

    2016-01-01

    Intracellular accumulation of the hyperphosphorylated tau is a pathological hallmark in the brain of Alzheimer disease. Activation of extrasynaptic NMDA receptors (E-NMDARs) induces excitatory toxicity that is involved in Alzheimer's neurodegeneration. However, the intrinsic link between E-NMDARs and the tau-induced neuronal damage remains elusive. In the present study, we showed in cultured primary cortical neurons that activation of E-NMDA receptors but not synaptic NMDA receptors dramatically increased tau mRNA and protein levels, with a simultaneous neuronal degeneration and decreased neuronal survival. Memantine, a selective antagonist of E-NMDARs, reversed E-NMDARs-induced tau overexpression. Activation of E-NMDARs in wild-type mouse brains resulted in neuron loss in hippocampus, whereas tau deletion in neuronal cultures and in the mouse brains rescued the E-NMDARs-induced neuronal death and degeneration. The E-NMDARs-induced tau overexpression was correlated with a reduced ERK phosphorylation, whereas the increased MEK activity, decreased binding and activity of ERK phosphatase to ERK, and increased ERK phosphorylation were observed in tau knockout mice. On the contrary, addition of tau proteins promoted ERK dephosphorylation in vitro. Taking together, these results indicate that tau overexpression mediates the excitatory toxicity induced by E-NMDAR activation through inhibiting ERK phosphorylation. PMID:27809304

  20. Effects of interferon-tau on cattle persistently infected with bovine viral diarrhea virus.

    PubMed

    Kohara, Junko; Nishikura, Yumiko; Konnai, Satoru; Tajima, Motoshi; Onuma, Misao

    2012-08-01

    In this study, the antiviral effects of bovine interferon-tau (boIFN-tau) on bovine viral diarrhea virus (BVDV) were examined in vitro and in vivo. In the in vitro experiments, the replication of cytopathic and non-cytopathic BVDV was inhibited in the bovine cells treated with boIFN-tau. The replication of BVDV was completely suppressed by boIFN-tau at a concentration higher than 10(2) U/ml. In order to examine the effect of boIFN-tau on virus propagation in cattle persistently infected (PI) with non-cytopathic BVDV, boIFN-tau was subcutaneously administered to PI cattle at 10(5) U/kg or 10(6) U/kg body weight 5 times per week for 2 weeks. No physical abnormality such as depression was observed in the cattle during the experiment. The mean BVDV titers in the serum of the PI cattle decreased slightly during the boIFN-tau administration period with the dose of 10(6) U/kg. However, the BVDV titers in the serum returned to the pre-administration level after the final boIFN-tau administration. These results suggest that boIFN-tau demonstrates an anti-BVDV effect, reducing the BVDV level in serum transiently when injected into PI cattle.

  1. Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

    PubMed

    Fá, M; Puzzo, D; Piacentini, R; Staniszewski, A; Zhang, H; Baltrons, M A; Li Puma, D D; Chatterjee, I; Li, J; Saeed, F; Berman, H L; Ripoli, C; Gulisano, W; Gonzalez, J; Tian, H; Costa, J A; Lopez, P; Davidowitz, E; Yu, W H; Haroutunian, V; Brown, L M; Palmeri, A; Sigurdsson, E M; Duff, K E; Teich, A F; Honig, L S; Sierks, M; Moe, J G; D'Adamio, L; Grassi, C; Kanaan, N M; Fraser, P E; Arancio, O

    2016-01-20

    Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.

  2. Michaelis-Menten speeds up tau-leaping under a wide range of conditions.

    PubMed

    Wu, Sheng; Fu, Jin; Cao, Yang; Petzold, Linda

    2011-04-07

    This paper examines the benefits of Michaelis-Menten model reduction techniques in stochastic tau-leaping simulations. Results show that although the conditions for the validity of the reductions for tau-leaping remain the same as those for the stochastic simulation algorithm (SSA), the reductions result in a substantial speed-up for tau-leaping under a different range of conditions than they do for SSA. The reason of this discrepancy is that the time steps for SSA and for tau-leaping are determined by different properties of system dynamics.

  3. Tau Deletion Prevents Stress-Induced Dendritic Atrophy in Prefrontal Cortex: Role of Synaptic Mitochondria.

    PubMed

    Lopes, Sofia; Teplytska, Larysa; Vaz-Silva, Joao; Dioli, Chrysoula; Trindade, Rita; Morais, Monica; Webhofer, Christian; Maccarrone, Giuseppina; Almeida, Osborne F X; Turck, Christoph W; Sousa, Nuno; Sotiropoulos, Ioannis; Filiou, Michaela D

    2016-04-12

    Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition, we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation as well as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.

  4. Search for astrophysical tau neutrinos in three years of IceCube data

    NASA Astrophysics Data System (ADS)

    Aartsen, M. G.; Abraham, K.; Ackermann, M.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Ahrens, M.; Altmann, D.; Anderson, T.; Ansseau, I.; Archinger, M.; Arguelles, C.; Arlen, T. C.; Auffenberg, J.; Bai, X.; Barwick, S. W.; Baum, V.; Bay, R.; Beatty, J. J.; Becker Tjus, J.; Becker, K.-H.; Beiser, E.; BenZvi, S.; Berghaus, P.; Berley, D.; Bernardini, E.; Bernhard, A.; Besson, D. Z.; Binder, G.; Bindig, D.; Bissok, M.; Blaufuss, E.; Blumenthal, J.; Boersma, D. J.; Bohm, C.; Börner, M.; Bos, F.; Bose, D.; Böser, S.; Botner, O.; Braun, J.; Brayeur, L.; Bretz, H.-P.; Buzinsky, N.; Casey, J.; Casier, M.; Cheung, E.; Chirkin, D.; Christov, A.; Clark, K.; Classen, L.; Coenders, S.; Cowen, D. F.; Cruz Silva, A. H.; Daughhetee, J.; Davis, J. C.; Day, M.; de André, J. P. A. M.; De Clercq, C.; del Pino Rosendo, E.; Dembinski, H.; De Ridder, S.; Desiati, P.; de Vries, K. D.; de Wasseige, G.; de With, M.; DeYoung, T.; Díaz-Vélez, J. C.; di Lorenzo, V.; Dumm, J. P.; Dunkman, M.; Eagan, R.; Eberhardt, B.; Ehrhardt, T.; Eichmann, B.; Euler, S.; Evenson, P. A.; Fadiran, O.; Fahey, S.; Fazely, A. R.; Fedynitch, A.; Feintzeig, J.; Felde, J.; Filimonov, K.; Finley, C.; Fischer-Wasels, T.; Flis, S.; Fösig, C.-C.; Fuchs, T.; Gaisser, T. K.; Gaior, R.; Gallagher, J.; Gerhardt, L.; Ghorbani, K.; Gier, D.; Gladstone, L.; Glagla, M.; Glüsenkamp, T.; Goldschmidt, A.; Golup, G.; Gonzalez, J. G.; Góra, D.; Grant, D.; Groh, J. C.; Groß, A.; Ha, C.; Haack, C.; Haj Ismail, A.; Hallgren, A.; Halzen, F.; Hansen, E.; Hansmann, B.; Hanson, K.; Hebecker, D.; Heereman, D.; Helbing, K.; Hellauer, R.; Hickford, S.; Hignight, J.; Hill, G. C.; Hoffman, K. D.; Hoffmann, R.; Holzapfel, K.; Homeier, A.; Hoshina, K.; Huang, F.; Huber, M.; Huelsnitz, W.; Hulth, P. O.; Hultqvist, K.; In, S.; Ishihara, A.; Jacobi, E.; Japaridze, G. S.; Jero, K.; Jurkovic, M.; Kappes, A.; Karg, T.; Karle, A.; Kauer, M.; Keivani, A.; Kelley, J. L.; Kemp, J.; Kheirandish, A.; Kiryluk, J.; Kläs, J.; Klein, S. R.; Kohnen, G.; Koirala, R.; Kolanoski, H.; Konietz, R.; Köpke, L.; Kopper, C.; Kopper, S.; Koskinen, D. J.; Kowalski, M.; Krings, K.; Kroll, G.; Kroll, M.; Kunnen, J.; Kurahashi, N.; Kuwabara, T.; Labare, M.; Lanfranchi, J. L.; Larson, M. J.; Lesiak-Bzdak, M.; Leuermann, M.; Leuner, J.; Lu, L.; Lünemann, J.; Madsen, J.; Maggi, G.; Mahn, K. B. M.; Maruyama, R.; Mase, K.; Matis, H. S.; Maunu, R.; McNally, F.; Meagher, K.; Medici, M.; Meli, A.; Menne, T.; Merino, G.; Meures, T.; Miarecki, S.; Middell, E.; Middlemas, E.; Mohrmann, L.; Montaruli, T.; Morse, R.; Nahnhauer, R.; Naumann, U.; Neer, G.; Niederhausen, H.; Nowicki, S. C.; Nygren, D. R.; Obertacke, A.; Olivas, A.; Omairat, A.; O'Murchadha, A.; Palczewski, T.; Pandya, H.; Pankova, D. V.; Paul, L.; Pepper, J. A.; Pérez de los Heros, C.; Pfendner, C.; Pieloth, D.; Pinat, E.; Posselt, J.; Price, P. B.; Przybylski, G. T.; Pütz, J.; Quinnan, M.; Raab, C.; Rädel, L.; Rameez, M.; Rawlins, K.; Reimann, R.; Relich, M.; Resconi, E.; Rhode, W.; Richman, M.; Richter, S.; Riedel, B.; Robertson, S.; Rongen, M.; Rott, C.; Ruhe, T.; Ryckbosch, D.; Saba, S. M.; Sabbatini, L.; Sander, H.-G.; Sandrock, A.; Sandroos, J.; Sarkar, S.; Schatto, K.; Scheriau, F.; Schimp, M.; Schmidt, T.; Schmitz, M.; Schoenen, S.; Schöneberg, S.; Schönwald, A.; Schulte, L.; Seckel, D.; Seunarine, S.; Smith, M. W. E.; Soldin, D.; Song, M.; Spiczak, G. M.; Spiering, C.; Stahlberg, M.; Stamatikos, M.; Stanev, T.; Stanisha, N. A.; Stasik, A.; Stezelberger, T.; Stokstad, R. G.; Stößl, A.; Ström, R.; Strotjohann, N. L.; Sullivan, G. W.; Sutherland, M.; Taavola, H.; Taboada, I.; Tatar, J.; Ter-Antonyan, S.; Terliuk, A.; Tešić, G.; Tilav, S.; Toale, P. A.; Tobin, M. N.; Toscano, S.; Tosi, D.; Tselengidou, M.; Turcati, A.; Unger, E.; Usner, M.; Vallecorsa, S.; Vandenbroucke, J.; van Eijndhoven, N.; Vanheule, S.; van Santen, J.; Veenkamp, J.; Vehring, M.; Voge, M.; Vraeghe, M.; Walck, C.; Wallace, A.; Wallraff, M.; Wandkowsky, N.; Weaver, Ch.; Wendt, C.; Westerhoff, S.; Whelan, B. J.; Whitehorn, N.; Wiebe, K.; Wiebusch, C. H.; Wille, L.; Williams, D. R.; Wissing, H.; Wolf, M.; Wood, T. R.; Woschnagg, K.; Xu, D. L.; Xu, X. W.; Xu, Y.; Yanez, J. P.; Yodh, G.; Yoshida, S.; Zoll, M.; IceCube Collaboration

    2016-01-01

    The IceCube Neutrino Observatory has observed a diffuse flux of TeV-PeV astrophysical neutrinos at 5.7 σ significance from an all-flavor search. The direct detection of tau neutrinos in this flux has yet to occur. Tau neutrinos become distinguishable from other flavors in IceCube at energies above a few hundred TeV, when the cascade from the tau neutrino charged current interaction becomes resolvable from the cascade from the tau lepton decay. This paper presents results from the first dedicated search for tau neutrinos with energies between 214 TeV and 72 PeV in the full IceCube detector. The analysis searches for IceCube optical sensors that observe two separate pulses in a single event—one from the tau neutrino interaction and a second from the tau decay. No candidate events were observed in three years of IceCube data. For the first time, a differential upper limit on astrophysical tau neutrinos is derived around the PeV energy region, which is nearly 3 orders of magnitude lower in energy than previous limits from dedicated tau neutrino searches.

  5. Halting of Caspase Activity Protects Tau from MC1-Conformational Change and Aggregation

    PubMed Central

    Mead, Emma; Kestoras, Dimitra; Gibson, Yolanda; Hamilton, Lucy; Goodson, Ross; Jones, Sophie; Eversden, Sarah; Davies, Peter; O’Neill, Michael; Hutton, Michael; Szekeres, Philip; Wolak, Joanna

    2016-01-01

    Intracellular neurofibrillary tangles (NFTs) are the hallmark of Alzheimer’s disease and other tauopathies in which tau, a microtubule-associated protein, loses its ability to stabilize microtubules. Several post-translational modifications including phosphorylation and truncation increase tau’s propensity to aggregate thus forming NFTs; however, the mechanisms underlying tau conformational change and aggregation still remain to be defined. Caspase activation and subsequent proteolytic cleavage of tau is thought to be a potential trigger of this disease-related pathological conformation. The aim of this work was to investigate the link between caspase activation and a disease-related conformational change of tau in a neuroblastoma cell-based model of spontaneous tau aggregation. We demonstrated that caspase induction initiates proteolytic cleavage of tau and generation of conformationally altered and aggregated tau recognized by the MC1 conformational antibody. Most importantly, these events were shown to be attenuated with caspase inhibitors. This implies that therapeutics aimed at inhibiting caspase-mediated tau cleavage may prove beneficial in slowing cleavage and aggregation, thus potentially halting tau pathology and disease progression. PMID:27589517

  6. Role of Tau, a microtubule associated protein, in Drosophila photoreceptor morphogenesis.

    PubMed

    Nam, Sang-Chul

    2016-11-01

    Cell polarity genes have important functions in photoreceptor morphogenesis. Based on recent discovery of stabilized microtubule cytoskeleton in developing photoreceptors and its role in photoreceptor cell polarity, microtubule associated proteins might have important roles in controlling cell polarity proteins' localizations in developing photoreceptors. Here, Tau, a microtubule associated protein, was analyzed to find its potential role in photoreceptor cell polarity. Tau colocalizes with acetylated/stabilized microtubules in developing pupal photoreceptors. Although it is known that tau mutant photoreceptor has no defects in early eye differentiation and development, it shows dramatic disruptions of cell polarity proteins, adherens junctions, and the stable microtubules in developing pupal photoreceptors. This role of Tau in cell polarity proteins' localization in photoreceptor cells during the photoreceptor morphogenesis was further supported by Tau's overexpression studies. Tau overexpression caused dramatic expansions of apical membrane domains where the polarity proteins localize in the developing pupal photoreceptors. It is also found that Tau's role in photoreceptor cell polarity depends on Par-1 kinase. Furthermore, a strong genetic interaction between tau and crumbs was found. It is found that Tau has a crucial role in cell polarity protein localization during pupal photoreceptor morphogenesis stage, but not in early eye development including eye cell differentiation.

  7. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

    PubMed

    Furgerson, Matthew; Fechheimer, Marcus; Furukawa, Ruth

    2012-01-01

    The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  8. Crystal Structures of the Glutamate Receptor Ion Channel GluK3 and GluK5 Amino-Terminal Domains

    SciTech Connect

    Kumar, Janesh; Mayer, Mark L.

    2010-11-30

    Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory synaptic neurotransmission in the central nervous system. The selective assembly of iGluRs into AMPA, kainate, and N-methyl-d-aspartic acid (NMDA) receptor subtypes is regulated by their extracellular amino-terminal domains (ATDs). Kainate receptors are further classified into low-affinity receptor families (GluK1-GluK3) and high-affinity receptor families (GluK4-GluK5) based on their affinity for the neurotoxin kainic acid. These two families share a 42% sequence identity for the intact receptor but only a 27% sequence identity at the level of ATD. We have determined for the first time the high-resolution crystal structures of GluK3 and GluK5 ATDs, both of which crystallize as dimers but with a strikingly different dimer assembly at the R1 interface. By contrast, for both GluK3 and GluK5, the R2 domain dimer assembly is similar to those reported previously for other non-NMDA iGluRs. This observation is consistent with the reports that GluK4-GluK5 cannot form functional homomeric ion channels and require obligate coassembly with GluK1-GluK3. Our analysis also reveals that the relative orientation of domains R1 and R2 in individual non-NMDA receptor ATDs varies by up to 10{sup o}, in contrast to the 50{sup o} difference reported for the NMDA receptor GluN2B subunit. This restricted domain movement in non-NMDA receptor ATDs seems to result both from extensive intramolecular contacts between domain R1 and domain R2 and from their assembly as dimers, which interact at both R1 and R2 domains. Our results provide the first insights into the structure and function of GluK4-GluK5, the least understood family of iGluRs.

  9. Interpreting EEG alpha activity.

    PubMed

    Bazanova, O M; Vernon, D

    2014-07-01

    Exploring EEG alpha oscillations has generated considerable interest, in particular with regards to the role they play in cognitive, psychomotor, psycho-emotional and physiological aspects of human life. However, there is no clearly agreed upon definition of what constitutes 'alpha activity' or which of the many indices should be used to characterize it. To address these issues this review attempts to delineate EEG alpha-activity, its physical, molecular and morphological nature, and examine the following indices: (1) the individual alpha peak frequency; (2) activation magnitude, as measured by alpha amplitude suppression across the individual alpha bandwidth in response to eyes opening, and (3) alpha "auto-rhythmicity" indices: which include intra-spindle amplitude variability, spindle length and steepness. Throughout, the article offers a number of suggestions regarding the mechanism(s) of alpha activity related to inter and intra-individual variability. In addition, it provides some insights into the various psychophysiological indices of alpha activity and highlights their role in optimal functioning and behavior.

  10. Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

    PubMed Central

    Ossola, Bernardino; Zhao, Chao; Compston, Alastair; Pluchino, Stefano; Franklin, Robin J. M.

    2015-01-01

    Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471 PMID:26576485

  11. WATER VAPOR IN THE PROTOPLANETARY DISK OF DG Tau

    SciTech Connect

    Podio, L.; Dougados, C.; Thi, W.-F.; Menard, F.; Pinte, C.; Codella, C.; Cabrit, S.; Nisini, B.; Sandell, G.; Williams, J. P.; Testi, L.; Woitke, P.

    2013-03-20

    Water is key in the evolution of protoplanetary disks and the formation of comets and icy/water planets. While high-excitation water lines originating in the hot inner disk have been detected in several T Tauri stars (TTSs), water vapor from the outer disk, where most water ice reservoirs are stored, was only reported in the nearby TTS TW Hya. We present spectrally resolved Herschel/HIFI observations of the young TTS DG Tau in the ortho- and para-water ground-state transitions at 557 and 1113 GHz. The lines show a narrow double-peaked profile, consistent with an origin in the outer disk, and are {approx}19-26 times brighter than in TW Hya. In contrast, CO and [C II] lines are dominated by emission from the envelope/outflow, which makes H{sub 2}O lines a unique tracer of the disk of DG Tau. Disk modeling with the thermo-chemical code ProDiMo indicates that the strong UV field, due to the young age and strong accretion of DG Tau, irradiates a disk upper layer at 10-90 AU from the star, heating it up to temperatures of 600 K and producing the observed bright water lines. The models suggest a disk mass of 0.015-0.1 M{sub Sun }, consistent with the estimated minimum mass of the solar nebula before planet formation, and a water reservoir of {approx}10{sup 2}-10{sup 3} Earth oceans in vapor and {approx}100 times larger in the form of ice. Hence, this detection supports the scenario of ocean delivery on terrestrial planets by the impact of icy bodies forming in the outer disk.

  12. Legendre-Tau approximations for functional differential equations

    NASA Technical Reports Server (NTRS)

    Ito, K.; Teglas, R.

    1983-01-01

    The numerical approximation of solutions to linear functional differential equations are considered using the so called Legendre tau method. The functional differential equation is first reformulated as a partial differential equation with a nonlocal boundary condition involving time differentiation. The approximate solution is then represented as a truncated Legendre series with time varying coefficients which satisfy a certain system of ordinary differential equations. The method is very easy to code and yields very accurate approximations. Convergence is established, various numerical examples are presented, and comparison between the latter and cubic spline approximations is made.

  13. A Search for Neutrinoless Tau Decays to Three Leptons

    SciTech Connect

    Kolb, Jeffrey A.

    2008-06-01

    Using approximately 350 million τ+τ- pair events recorded with the BaBar detector at the Stanford Linear Accelerator Center between 1999 and 2006, a search has been made for neutrinoless, lepton-flavor violating tau decays to three lighter leptons. All six decay modes consistent with conservation of electric charge and energy have been considered. With signal selection efficiencies of 5-12%, we obtain 90% confidence level upper limits on the branching fraction β}(τ → ℓℓℓ) in the range (4-8) x 10-8.

  14. Selections from 2016: Gaps in HL Tau's Protoplanetary Disk

    NASA Astrophysics Data System (ADS)

    Kohler, Susanna

    2016-12-01

    Editors note:In these last two weeks of 2016, well be looking at a few selections that we havent yet discussed on AAS Nova from among the most-downloaded paperspublished in AAS journals this year. The usual posting schedule will resume after the AAS winter meeting.Gas Gaps in the Protoplanetary Disk Around the Young Protostar HL TauPublished March 2016The dust (left) and gas (right) emission from HL Tau show that the gaps in its disk match up. [Yen et al. 2016]Main takeaway:At the end of last year, the Atacama Large Millimeter/Submillimeter Array released some of its first data including a spectacular observation of a dusty protoplanetary disk around the young star HL Tau. In this follow-up study, a team led by Hsi-Wei Yen (Academia Sinica Institute of Astronomy and Astrophysics, Taiwan) analyzed the ALMA data and confirmed the presence of two gaps in the gas of HL Taus disk, at radii of 28 and 69 AU.Why its interesting:The original ALMA image of HL Taus disk suggests the presence of gaps in disk, but scientists werent sure if they were caused by effects like gravitational instabilities or dust clumping, or if the gaps were created by the presence of young planets. Yen and collaborators showed that gaps in the disks gas line up with gaps in its dust, supporting the model in which these gaps have been carved out by newly formed planets.Added intrigue:The evidence for planets in this disk came as a bit of a surprise, since it was originally believed that it takes tens of millions of years to form planets from the dust of protoplanetary disks but HL Tau is only a million years old. These observations therefore suggest that planets start to form much earlier than we thought.CitationHsi-Wei Yen et al 2016 ApJL 820 L25. doi:10.3847/2041-8205/820/2/L25

  15. Charmonium physics at a tau-charm factory

    SciTech Connect

    Barnes, T. |

    1993-11-01

    Since its discovery in 1974 the charmonium system has served hadron physics as an important arena for the investigation of many aspects of QCD and hadron spectroscopy. In this summary the author briefly reviews some of these and discusses several of the important outstanding issues in hadron spectroscopy and their relation to the spectrum and couplings of resonances in the charmonium system. The topics discussed are charmonium spectroscopy, electromagnetic couplings ({gamma}, {gamma}{gamma} and e{sup +}e{sup {minus}}), strong decays and unusual states (charm molecules and charmonium hybrids), and in each case the author notes areas in which experiments at a tau-charm factory could make valuable contributions.

  16. Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid

    PubMed Central

    Voyle, Nicola; Patel, Hamel; Folarin, Amos; Newhouse, Stephen; Johnston, Caroline; Visser, Pieter Jelle; Dobson, Richard J.B.; Kiddle, Steven J.

    2016-01-01

    Background: The search for a biomarker of Alzheimer’s disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau. Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF. Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype (‘basic model’). Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%). Conclusion: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors

  17. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons.

    PubMed

    Lacovich, Valentina; Espindola, Sonia L; Alloatti, Matías; Pozo Devoto, Victorio; Cromberg, Lucas; Čarná, Mária; Forte, Giancarlo; Gallo, Jean-Marc; Bruno, Luciana; Stokin, Gorazd B; Avale, M Elena; Falzone, Tomás L

    2016-11-11

    Tau, as a microtubule-associated protein, participates in key neuronal functions such as the regulation of microtubule dynamics, axonal transport and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) microtubule binding repeats. While tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated to the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here we addressed this question using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectories analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP-vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Contrarely, the imbalance towards the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoforms imbalances with APP abnormal metabolism in neurodegenerative processes.

  18. Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons.

    PubMed

    Lacovich, Valentina; Espindola, Sonia L; Alloatti, Matías; Pozo Devoto, Victorio; Cromberg, Lucas E; Čarná, Mária E; Forte, Giancarlo; Gallo, Jean-Marc; Bruno, Luciana; Stokin, Gorazd B; Avale, M Elena; Falzone, Tomás L

    2017-01-04

    Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.

  19. Tau excess impairs mitosis and kinesin-5 function, leading to aneuploidy and cell death.

    PubMed

    Bougé, Anne-Laure; Parmentier, Marie-Laure

    2016-03-01

    In neurodegenerative diseases such as Alzheimer's disease (AD), cell cycle defects and associated aneuploidy have been described. However, the importance of these defects in the physiopathology of AD and the underlying mechanistic processes are largely unknown, in particular with respect to the microtubule (MT)-binding protein Tau, which is found in excess in the brain and cerebrospinal fluid of affected individuals. Although it has long been known that Tau is phosphorylated during mitosis to generate a lower affinity for MTs, there is, to our knowledge, no indication that an excess of this protein could affect mitosis. Here, we studied the effect of an excess of human Tau (hTau) protein on cell mitosis in vivo. Using the Drosophila developing wing disc epithelium as a model, we show that an excess of hTau induces a mitotic arrest, with the presence of monopolar spindles. This mitotic defect leads to aneuploidy and apoptotic cell death. We studied the mechanism of action of hTau and found that the MT-binding domain of hTau is responsible for these defects. We also demonstrate that the effects of hTau occur via the inhibition of the function of the kinesin Klp61F, the Drosophila homologue of kinesin-5 (also called Eg5 or KIF11). We finally show that this deleterious effect of hTau is also found in other Drosophila cell types (neuroblasts) and tissues (the developing eye disc), as well as in human HeLa cells. By demonstrating that MT-bound Tau inhibits the Eg5 kinesin and cell mitosis, our work provides a new framework to consider the role of Tau in neurodegenerative diseases.

  20. Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport.

    PubMed

    Le, Michelle H; Weissmiller, April M; Monte, Louise; Lin, Po Han; Hexom, Tia C; Natera, Orlangie; Wu, Chengbiao; Rissman, Robert A

    2016-01-01

    Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD), the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr) and chronic (2hr) CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF), this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD.