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https://www.readbyqxmd.com/read/28527208/neuronal-expression-of-truncated-tau-efficiently-promotes-neurodegeneration-in-animal-models-pitfalls-of-toxic-oligomer-analysis
#1
Rostislav Skrabana, Branislav Kovacech, Peter Filipcik, Norbert Zilka, Santosh Jadhav, Tomas Smolek, Eva Kontsekova, Michal Novak
Animal models of neurodegeneration induced by neuronal expression of truncated tau protein emerge as an important tool for understanding the pathogenesis of human tauopathies and for therapy development. Here we highlight common features of truncated tau models and make a critical assessment of possible pitfalls in their analysis. Particularly, the amount of soluble tau oligomers, which are suspected to be neurotoxic agents participating on the spreading of pathology inside the brain, may be overestimated due to a post-lysis oxidative tau oligomerization...
May 17, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28524178/transcriptome-analyses-of-chronic-traumatic-encephalopathy-show-alterations-in-protein-phosphatase-expression-associated-with-tauopathy
#2
Jeong-Sun Seo, Seungbok Lee, Jong-Yeon Shin, Yu Jin Hwang, Hyesun Cho, Seong-Keun Yoo, Yunha Kim, Sungsu Lim, Yun Kyung Kim, Eun Mi Hwang, Su Hyun Kim, Chong-Hyun Kim, Seung Jae Hyeon, Ji-Young Yun, Jihye Kim, Yona Kim, Victor E Alvarez, Thor D Stein, Junghee Lee, Dong Jin Kim, Jong-Il Kim, Neil W Kowall, Hoon Ryu, Ann C McKee
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE...
May 19, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28523532/progressive-pathological-changes-in-neurochemical-profile-of-the-hippocampus-and-early-changes-in-the-olfactory-bulbs-of-tau-transgenic-mice-rtg4510
#3
Jieun Kim, In-Young Choi, Karen E Duff, Phil Lee
Tauopathies such as Alzheimer's disease and frontotemporal lobe degeneration (FTLD-tau) dementia, characterized by pathologic aggregation of the microtubule-associated tau protein and formation of neurofibrillary tangles, have been linked to neurodegeneration and cognitive decline. The early detection of cerebral abnormalities and the identification of biological contributors to the continuous pathologic processes of neurodegeneration in tauopathies critically hinge on sensitive and reliable measures of biomarkers in the living brain...
May 18, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28521765/inhibition-of-o-glcnacase-leads-to-elevation-of-o-glcnac-tau-and-reduction-of-tauopathy-and-cerebrospinal-fluid-tau-in-rtg4510-mice
#4
Nicholas B Hastings, Xiaohai Wang, Lixin Song, Brent D Butts, Diane Grotz, Richard Hargreaves, J Fred Hess, Kwok-Lam Karen Hong, Cathy Ruey-Ruey Huang, Lynn Hyde, Maureen Laverty, Julie Lee, Diane Levitan, Sherry X Lu, Maureen Maguire, Veeravan Mahadomrongkul, Ernest J McEachern, Xuesong Ouyang, Thomas W Rosahl, Harold Selnick, Michaela Stanton, Giuseppe Terracina, David J Vocadlo, Ganfeng Wang, Joseph L Duffy, Eric M Parker, Lili Zhang
BACKGROUND: Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models...
May 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28507319/longitudinal-changes-of-tau-pet-imaging-in-relation-to-hypometabolism-in-prodromal-and-alzheimer-s-disease-dementia
#5
K Chiotis, L Saint-Aubert, E Rodriguez-Vieitez, A Leuzy, O Almkvist, I Savitcheva, M Jonasson, M Lubberink, A Wall, G Antoni, A Nordberg
The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [(18)F]THK5317 (tau deposition) and [(18)F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [(11)C]PIB (amyloid-β deposition) at baseline only...
May 16, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28506438/prion-like-spreading-in-tauopathies
#6
REVIEW
Jacob I Ayers, Benoit I Giasson, David R Borchelt
Tau is a microtubule-associated protein that functions in regulating cytoskeleton dynamics, especially in neurons. Misfolded and aggregated forms of tau produce pathological structures in a number of neurodegenerative diseases, including Alzheimer's disease (AD) and tauopathy dementias. These disorders can present with a sporadic etiology, such as in AD, or a familial etiology, such as in some cases of frontotemporal dementia with parkinsonism. Notably, the pathological features of tau pathology in these diseases can be very distinct...
April 13, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28502805/distinct-phenotypes-of-three-repeat-and-four-repeat-human-tau-in-a-transgenic-model-of-tauopathy
#7
Megan A Sealey, Ergina Vourkou, Catherine M Cowan, Torsten Bossing, Shmma Quraishe, Sofia Grammenoudi, Efthimios M C Skoulakis, Amritpal Mudher
Tau exists as six closely related protein isoforms in the adult human brain. These are generated from alternative splicing of a single mRNA transcript and they differ in the absence or presence of two N-terminal and three or four microtubule binding domains. Typically all six isoforms have been considered functionally similar. However, their differential involvement in particular tauopathies raises the possibility that there may be isoform-specific differences in physiological function and pathological role...
May 11, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28500878/identification-of-changes-in-neuronal-function-as-a-consequence-of-aging-and-tauopathic-neurodegeneration-using-a-novel-and-sensitive-magnetic-resonance-imaging-approach
#8
Sarah N Fontaine, Alexandria Ingram, Ryan A Cloyd, Shelby E Meier, Emily Miller, Danielle Lyons, Grant K Nation, Elizabeth Mechas, Blaine Weiss, Chiara Lanzillotta, Fabio Di Domenico, Frederick Schmitt, David K Powell, Moriel Vandsburger, Jose F Abisambra
Tauopathies, the most common of which is Alzheimer's disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process...
April 18, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28500751/radiological-biomarkers-for-diagnosis-in-psp-where-are-we-and-where-do-we-need-to-be
#9
REVIEW
Jennifer L Whitwell, Günter U Höglinger, Angelo Antonini, Yvette Bordelon, Adam L Boxer, Carlo Colosimo, Thilo van Eimeren, Lawrence I Golbe, Jan Kassubek, Carolin Kurz, Irene Litvan, Alexander Pantelyat, Gil Rabinovici, Gesine Respondek, Axel Rominger, James B Rowe, Maria Stamelou, Keith A Josephs
BACKGROUND: PSP is a pathologically defined neurodegenerative tauopathy with a variety of clinical presentations including typical Richardson's syndrome and other variant PSP syndromes. Our aim was to critically evaluate the degree to which structural, functional and molecular neuroimaging metrics fulfill criteria for diagnostic biomarkers of PSP. METHODS: We queried the PubMed, Cochrane, Medline, and PSYCInfo databases for original research articles published in English using postmortem diagnosis or NINDS-SPSP criteria as the diagnostic standard from 1996-2016...
May 13, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28498801/extracellular-truncated-tau-causes-early-presynaptic-dysfunction-associated-with-alzheimer-s-disease-and-other-tauopathies
#10
Fulvio Florenzano, Corsetti Veronica, Gabriele Ciasca, Maria Teresa Ciotti, Anna Pittaluga, Gunedalina Olivero, Marco Feligioni, Filomena Iannuzzi, Valentina Latina, Michele Francesco Maria Sciacca, Alessandro Sinopoli, Danilo Milardi, Giuseppe Pappalardo, Marco De Spirito, Massimiliano Papi, Anna Atlante, Antonella Bobba, Antonella Borreca, Pietro Calissano, Giuseppina Amadoro
The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2-derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer's disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2tau 26-44 (aka NH2htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+-evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics...
April 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28493068/cathepsin-s-increases-tau-oligomer-formation-through-limited-cleavage-but-only-il-6-not-cathespin-s-serum-levels-correlate-with-disease-severity-in-the-neurodegenerative-tauopathy-progressive-supranuclear-palsy
#11
Georg Nübling, M Schuberth, K Feldmer, A Giese, L M Holdt, D Teupser, S Lorenzl
Limited cleavage promotes the aggregation propensity of protein tau in neurodegenerative tauopathies. Cathepsin S (CatS) is overexpressed in brains of patients suffering from tauopathies such as Alzheimer's disease (AD). Furthermore, CatS serum levels correlate with survival in the elderly. The current study investigates whether limited cleavage by CatS promotes tau aggregation, and whether CatS serum levels may correlate with disease severity in tauopathies. Oligomer formation of fluorescently labeled protein tau was monitored by single particle fluorescence spectroscopy after coincubation with CatS...
May 10, 2017: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/28492240/tau-association-with-synaptic-vesicles-causes-presynaptic-dysfunction
#12
Lujia Zhou, Joseph McInnes, Keimpe Wierda, Matthew Holt, Abigail G Herrmann, Rosemary J Jackson, Yu-Chun Wang, Jef Swerts, Jelle Beyens, Katarzyna Miskiewicz, Sven Vilain, Ilse Dewachter, Diederik Moechars, Bart De Strooper, Tara L Spires-Jones, Joris De Wit, Patrik Verstreken
Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons...
May 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28487370/transactive-response-dna-binding-protein-43-tdp-43-regulates-alternative-splicing-of-tau-exon-10-implications-for-the-pathogenesis-of-tauopathies
#13
Jianlan Gu, Feng Chen, Khalid Iqbal, Cheng-Xin Gong, Xinglong Wang, Fei Liu
Hyperphosphorylation and aggregation of the neuronal protein tau is responsible for neurodegenerative diseases called tauopathies. Dysregulation of the alternative splicing of the exon 10 results in alterations of the ratio of two tau isoforms, 3R-tau and 4R-tau, which have been seen in several tauopathies. Transactive response DNA-binding protein 43 kDa (TDP-43) is involved in the regulation of RNA processing, including splicing. Cytoplasmic aggregation of TDP-43 has been observed in the brains of individuals with chronic traumatic encephalopathy or Alzheimer's disease, diseases in which neurofibrillary tangles of hyperphosphorylated tau are hallmarks...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28483344/the-exceptional-vulnerability-of-humans-to-alzheimer-s-disease
#14
REVIEW
Lary C Walker, Mathias Jucker
Like many humans, non-human primates deposit copious misfolded Aβ protein in the brain as they age. Nevertheless, the complete behavioral and pathologic phenotype of Alzheimer's disease, including Aβ plaques, neurofibrillary (tau) tangles, and dementia, has not yet been identified in a non-human species. Recent research suggests that the crucial link between Aβ aggregation and tauopathy is somehow disengaged in aged monkeys. Understanding why Alzheimer's disease fails to develop in species that are biologically proximal to humans could disclose new therapeutic targets in the chain of events leading to neurodegeneration and dementia...
May 5, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28482642/extracellular-tau-oligomers-induce-invasion-of-endogenous-tau-into-the-somatodendritic-compartment-and-axonal-transport-dysfunction
#15
Eric Swanson, Leigham Breckenridge, Lloyd McMahon, Sreemoyee Som, Ian McConnell, George S Bloom
Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer's disease and non-Alzheimer's tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology...
May 5, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28473694/accumulation-of-multiple-neurodegenerative-disease-related-proteins-in-familial-frontotemporal-lobar-degeneration-associated-with-granulin-mutation
#16
Masato Hosokawa, Hiromi Kondo, Geidy E Serrano, Thomas G Beach, Andrew C Robinson, David M Mann, Haruhiko Akiyama, Masato Hasegawa, Tetsuaki Arai
In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation...
May 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28472993/humanized-monoclonal-antibody-armanezumab-specific-to-n-terminus-of-pathological-tau-characterization-and-therapeutic-potency
#17
Michael G Agadjanyan, Karen Zagorski, Irina Petrushina, Hayk Davtyan, Konstantin Kazarian, Maxim Antonenko, Joy Davis, Charles Bon, Mathew Blurton-Jones, David H Cribbs, Anahit Ghochikyan
BACKGROUND: The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2-18 termed "phosphatase activation domain" that is normally hidden in the native protein in 'paperclip'-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau...
May 5, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28466265/ips-cell-cultures-from-a-gerstmann-str%C3%A3-ussler-scheinker-patient-with-the-y218n-prnp-mutation-recapitulate-tau-pathology
#18
Andreu Matamoros-Angles, Lucía Mayela Gayosso, Yvonne Richaud-Patin, Angelique di Domenico, Cristina Vergara, Arnau Hervera, Amaya Sousa, Natalia Fernández-Borges, Antonella Consiglio, Rosalina Gavín, Rakel López de Maturana, Isidro Ferrer, Adolfo López de Munain, Ángel Raya, Joaquín Castilla, Rosario Sánchez-Pernaute, José Antonio Del Río
Gerstmann-Sträussler-Scheinker (GSS) syndrome is a fatal autosomal dominant neurodegenerative prionopathy clinically characterized by ataxia, spastic paraparesis, extrapyramidal signs and dementia. In some GSS familiar cases carrying point mutations in the PRNP gene, patients also showed comorbid tauopathy leading to mixed pathologies. In this study we developed an induced pluripotent stem (iPS) cell model derived from fibroblasts of a GSS patient harboring the Y218N PRNP mutation, as well as an age-matched healthy control...
May 2, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28461218/cerebrospinal-fluid-neurofilament-light-chain-as-a-biomarker-of-neurodegeneration-in-the-tg4510-and-mitopark-mouse-models
#19
Amalie Clement, Cathy Mitchelmore, Daniel R Andersson, Ayodeji A Asuni
A challenge in working with preclinical models of neurodegeneration has been how to non-invasively monitor disease progression. Neurofilament proteins are established axonal damage markers and have been found to be elevated in cerebrospinal fluid (CSF) and blood from patients with neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies. We hypothesized that CSF neurofilament light (NF-L) can be used to track progression of neurodegeneration and potentially monitor the efficacy of novel therapeutic agents in preclinical development...
April 28, 2017: Neuroscience
https://www.readbyqxmd.com/read/28461004/disruption-of-normal-circadian-clock-function-in-a-mouse-model-of-tauopathy
#20
Korey Stevanovic, Amara Yunus, Aurelie Joly-Amado, Marcia Gordon, David Morgan, Danielle Gulick, Joshua Gamsby
Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to β-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock...
April 28, 2017: Experimental Neurology
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