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https://www.readbyqxmd.com/read/28318914/systemic-and-network-functions-of-the-microtubule-associated-protein-tau-implications-for-tau-based-therapies
#1
REVIEW
Lidia Bakota, Abdala Ussif, Gunnar Jeserich, Roland Brandt
Tau is a microtubule-associated neuronal protein, whose primary role was long thought to regulate axonal microtubule assembly. Tau is subject to many posttranslational modifications and can aggregate into neurofibrillary tangles, which are considered to be a hallmark of several neurodegenerative diseases collectively called "tauopathies". The most common tauopathy is Alzheimer's disease, where tau pathology correlates with sites of neurodegeneration. Tau belongs to the class of intrinsically disordered proteins, which are known to interact with many partners and are considered to be involved in various signaling, regulation and recognition processes...
March 16, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28315409/in-vivo-tau-pet-imaging-in-dementia-pathophysiology-radiotracer-quantification-and-a-systematic-review-of-clinical-findings
#2
REVIEW
Benjamin Hall, Elijah Mak, Simon Cervenka, Franklin I Aigbirhio, James B Rowe, John T O'Brien
In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging...
March 14, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28303942/signature-of-an-aggregation-prone-conformation-of-tau
#3
Neil A Eschmann, Elka R Georgieva, Pritam Ganguly, Peter P Borbat, Maxime D Rappaport, Yasar Akdogan, Jack H Freed, Joan-Emma Shea, Songi Han
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...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300838/membrane-association-and-release-of-wild-type-and-pathological-tau-from-organotypic-brain-slice-cultures
#4
Cara L Croft, Matthew A Wade, Ksenia Kurbatskaya, Pavlina Mastrandreas, Martina M Hughes, Emma C Phillips, Amy M Pooler, Michael S Perkinton, Diane P Hanger, Wendy Noble
The spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer's disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those involved in the spread of pathological tau species. To begin to understand these events, we have studied tau distribution and release using organotypic brain slice cultures...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28298428/autoantibodies-to-synaptic-receptors-and-neuronal-cell-surface-proteins-in-autoimmune-diseases-of-the-central-nervous-system
#5
REVIEW
Josep Dalmau, Christian Geis, Francesc Graus
Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all characterized by autoantibodies against neuronal proteins involved in synaptic signaling and plasticity. In clinical practice these findings have changed the diagnostic and treatment approach to potentially lethal, but now treatable, neurological and psychiatric syndromes previously considered idiopathic or not even suspected to be immune-mediated...
April 2017: Physiological Reviews
https://www.readbyqxmd.com/read/28293793/ultrasensitive-and-selective-detection-of-3-repeat-tau-seeding-activity-in-pick-disease-brain-and-cerebrospinal-fluid
#6
Eri Saijo, Bernardino Ghetti, Gianluigi Zanusso, Adrian Oblak, Jennifer L Furman, Marc I Diamond, Allison Kraus, Byron Caughey
The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10(-7)-10(-9)...
March 14, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28287136/a-dual-pathogenic-mechanism-links-tau-acetylation-to-sporadic-tauopathy
#7
Hanna Trzeciakiewicz, Jui-Heng Tseng, Connor M Wander, Victoria Madden, Ashutosh Tripathy, Chao-Xing Yuan, Todd J Cohen
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...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28281308/overlapping-but-distinct-tdp-43-and-tau-pathologic-patterns-in-aged-hippocampi
#8
Vanessa D Smith, Adam D Bachstetter, Eseosa Ighodaro, Kelly Roberts, Erin L Abner, David W Fardo, Peter T Nelson
Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration...
March 9, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28275652/altered-sleep-and-eeg-power-in-the-p301s-tau-transgenic-mouse-model
#9
Jerrah K Holth, Thomas E Mahan, Grace O Robinson, Andreia Rocha, David M Holtzman
OBJECTIVE: Sleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice. METHODS: P301S and wild-type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response...
March 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28271184/shared-genetic-risk-between-corticobasal-degeneration-progressive-supranuclear-palsy-and-frontotemporal-dementia
#10
Jennifer S Yokoyama, Celeste M Karch, Chun C Fan, Luke W Bonham, Naomi Kouri, Owen A Ross, Rosa Rademakers, Jungsu Kim, Yunpeng Wang, Günter U Höglinger, Ulrich Müller, Raffaele Ferrari, John Hardy, Parastoo Momeni, Leo P Sugrue, Christopher P Hess, A James Barkovich, Adam L Boxer, William W Seeley, Gil D Rabinovici, Howard J Rosen, Bruce L Miller, Nicholas J Schmansky, Bruce Fischl, Bradley T Hyman, Dennis W Dickson, Gerard D Schellenberg, Ole A Andreassen, Anders M Dale, Rahul S Desikan
Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD...
March 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28269786/dietary-lycopene-supplementation-improves-cognitive-performances-in-tau-transgenic-mice-expressing-p301l-mutation-via-inhibiting-oxidative-stress-and-tau-hyperphosphorylation
#11
Lixia Yu, Weiguang Wang, Wei Pang, Zhonghai Xiao, Yugang Jiang, Yan Hong
BACKGROUND: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress. OBJECTIVE: The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation...
February 25, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28267200/microtubule-dynamics-and-the-neurodegenerative-triad-of-alzheimer-s-disease-the-hidden-connection
#12
REVIEW
Roland Brandt, Lidia Bakota
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is, on a histopathological level, characterized by the presence of extracellular amyloid plaques composed of the protein fragment Aβ, and intracellular neurofibrillary tangles (NFTs), which contain the microtubule-associated protein tau in a hyperphosphorylated state. In AD defects in microtubule (MT) assembly and organization have also been reported; however, it is unclear whether MT abnormalities have a causal and early role in the disease process or represent a common end point downstream of the neurodegenerative cascade...
March 7, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28266613/screening-with-an-nmnat2-msd-platform-identifies-small-molecules-that-modulate-nmnat2-levels-in-cortical-neurons
#13
Yousuf O Ali, Gillian Bradley, Hui-Chen Lu
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28254594/the-current-status-of-research-on-chronic-traumatic-encephalopathy
#14
REVIEW
Kenneth Perrine, Jacqueline Helcer, Apostolos John Tsiouris, David J Pisapia, Philip Stieg
Chronic Traumatic Encephalopathy (CTE) evolved from the term "dementia pugilistica" describing the dementia found in many boxers to its current use in describing the dementia and depression sometimes found in athletes subjected to multiple concussions or sub-concussive blows to the head. Concurrently, the neuropathology evolved to specify a unique type of tauopathy found in perivascular spaces at the depth of sulci and other features not typically seen in neurodegenerative tauopathies. Four stages of CTE have been proposed, with four corresponding clinical syndromes of Traumatic Encephalopathy Syndrome...
February 27, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28253546/fdg-metabolism-associated-with-tau-amyloid-interaction-predicts-memory-decline
#15
Bernard J Hanseeuw, Rebecca A Betensky, Aaron P Schultz, Kate V Papp, Elizabeth C Mormino, Jorge Sepulcre, John S Bark, Danielle M Cosio, Molly LaPoint, Jasmeer P Chhatwal, Dorene M Rentz, Reisa A Sperling, Keith Johnson
OBJECTIVE: To evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. METHODS: We acquired positron emission tomography using F18 Flortaucipir (tau), C11 Pittsburgh Compound B (amyloid) and F18 Fluorodeoxyglucose in 90 clinically normal elderly of the Harvard Aging Brain Study. RESULTS: Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly...
March 2, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28236445/the-heidenhain-variant-of-creutzfeldt-jakob-disease-and-concomitant-tau-pathology-a-case-report
#16
Edvard Ehler, Michael Pipka, Alena Meleková, Petra Mandysová, Silvie Johanidesová, Radoslav Matěj, Robert Rusina
The Heidenhain form of Creutzfeldt-Jakob disease (CJD) is a rare CJD variant with predominantly visual symptoms in the early stages. Clinical manifestations of metamorphopsia, hemianopia and Balint's syndrome correlate with the involvement of the posterior cortical regions. A 71-year old healthy and very active man was admitted because of impaired visual acuity, hemianopia, and gait disturbance progressing over one week. MRI found typical cortical hyperintensities in the occipital regions while rhythm slowing and sharp waves were seen in the occipital regions on EEG...
February 10, 2017: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/28229128/repetitive-head-impact-exposure-and-later-life-plasma-total-tau-in-former-national-football-league-players
#17
Michael L Alosco, Yorghos Tripodis, Johnny Jarnagin, Christine M Baugh, Brett Martin, Christine E Chaisson, Nate Estochen, Linan Song, Robert C Cantu, Andreas Jeromin, Robert A Stern
INTRODUCTION: Blood protein analysis of total tau (t-tau) may be a practical screening biomarker for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. We examined plasma t-tau in symptomatic former National Football League (NFL) players compared with controls and the relationship between RHI exposure and later-life plasma t-tau. METHODS: Ninety-six former NFL players (age 40-69) and 25 same-age controls underwent blood draw to determine plasma t-tau levels...
2017: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/28224671/outcomes-after-diagnosis-of-mild-cognitive-impairment-in-a-large-autopsy-series
#18
Erin L Abner, Richard J Kryscio, Frederick A Schmitt, David W Fardo, Daniela C Moga, Eseosa T Ighodaro, Gregory A Jicha, Lei Yu, Hiroko H Dodge, Chengjie Xiong, Randall L Woltjer, Julie A Schneider, Nigel J Cairns, David A Bennett, Peter T Nelson
OBJECTIVE: Determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). METHODS: Data were drawn from a large autopsy series (N=1,337) of individuals followed longitudinally from normal or MCI status to death, derived from four Alzheimer's Disease (AD) Centers in the United States. RESULTS: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39...
February 22, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28222529/progressive-motor-deficit-is-mediated-by-the-denervation-of-neuromuscular-junctions-and-axonal-degeneration-in-transgenic-mice-expressing-mutant-p301s-tau-protein
#19
Zhuoran Yin, Femke Valkenburg, Betty E Hornix, Ietje Mantingh-Otter, Xingdong Zhou, Muriel Mari, Fulvio Reggiori, Debby Van Dam, Bart J L Eggen, Peter P De Deyn, Erik Boddeke
Tauopathies include a variety of neurodegenerative diseases associated with the pathological aggregation of hyperphosphorylated tau, resulting in progressive cognitive decline and motor impairment. The underlying mechanism for motor deficits related to tauopathy is not yet fully understood. Here, we use a novel transgenic tau mouse line, Tau 58/4, with enhanced neuron-specific expression of P301S mutant tau to investigate the motor abnormalities in association with the peripheral nervous system. Using stationary beam, gait, and rotarod tests, motor deficits were found in Tau 58/4 mice already 3 months after birth, which deteriorated during aging...
February 10, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28219440/tau-pet-imaging-present-and-future-directions
#20
REVIEW
Laure Saint-Aubert, Laetitia Lemoine, Konstantinos Chiotis, Antoine Leuzy, Elena Rodriguez-Vieitez, Agneta Nordberg
Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3...
February 20, 2017: Molecular Neurodegeneration
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