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Tau oligomers

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https://www.readbyqxmd.com/read/28533388/selective-lowering-of-synapsins-induced-by-oligomeric-%C3%AE-synuclein-exacerbates-memory-deficits
#1
Megan E Larson, Susan J Greimel, Fatou Amar, Michael LaCroix, Gabriel Boyle, Mathew A Sherman, Hallie Schley, Camille Miel, Julie A Schneider, Rakez Kayed, Fabio Benfenati, Michael K Lee, David A Bennett, Sylvain E Lesné
Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28528849/extracellular-low-n-oligomers-of-tau-cause-selective-synaptotoxicity-without-affecting-cell-viability
#2
Senthilvelrajan Kaniyappan, Ram Reddy Chandupatla, Eva-Maria Mandelkow, Eckhard Mandelkow
INTRODUCTION: Tau-mediated toxicity in Alzheimer's disease is thought to operate through low-n oligomers, rather than filamentous aggregates. However, the nature of oligomers and pathways of toxicity are poorly understood. Therefore, we investigated structural and functional aspects of highly purified oligomers of a pro-aggregant tau species. METHODS: Purified oligomers of the tau repeat domain were characterized by biophysical and structural methods. Functional aspects were investigated by cellular assays ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) bromide assay of cell viability, lactate dehydrogenase release assay [for cell toxicity], reactive oxygen species production, and calcium assay), combined with analysis of neuronal dendritic spines exposed to oligomers...
May 18, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28527208/neuronal-expression-of-truncated-tau-efficiently-promotes-neurodegeneration-in-animal-models-pitfalls-of-toxic-oligomer-analysis
#3
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/28519902/reduced-gliotransmitter-release-from-astrocytes-mediates-tau-induced-synaptic-dysfunction-in-cultured-hippocampal-neurons
#4
Roberto Piacentini, Domenica Donatella Li Puma, Marco Mainardi, Giacomo Lazzarino, Barbara Tavazzi, Ottavio Arancio, Claudio Grassi
Tau is a microtubule-associated protein exerting several physiological functions in neurons. In Alzheimer's disease (AD) misfolded tau accumulates intraneuronally and leads to axonal degeneration. However, tau has also been found in the extracellular medium. Recent studies indicated that extracellular tau uploaded from neurons causes synaptic dysfunction and contributes to tau pathology propagation. Here we report novel evidence that extracellular tau oligomers are abundantly and rapidly accumulated in astrocytes where they disrupt intracellular Ca(2+) signaling and Ca(2+) -dependent release of gliotransmitters, especially ATP...
May 18, 2017: Glia
https://www.readbyqxmd.com/read/28509380/amyloid-is-essential-but-insufficient-for-alzheimer-causation-addition-of-subcellular-cofactors-is-required-for-dementia
#5
REVIEW
Jeffrey Fessel
OBJECTIVE: The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD). METHODS: Published studies were examined. RESULTS: The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid-centric treatments have provided no clinical benefit and about one-third of cognitively normal, older persons have cerebral amyloid plaques...
May 16, 2017: International Journal of Geriatric Psychiatry
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
#6
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/28487416/the-amyloid-%C3%AE-oligomer-a%C3%AE-56-induces-specific-alterations-in-neuronal-signaling-that-lead-to-tau-phosphorylation-and-aggregation
#7
Fatou Amar, Mathew A Sherman, Travis Rush, Megan Larson, Gabriel Boyle, Liu Chang, Jürgen Götz, Alain Buisson, Sylvain E Lesné
Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Aβ) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ*56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling...
May 9, 2017: Science Signaling
https://www.readbyqxmd.com/read/28482642/extracellular-tau-oligomers-induce-invasion-of-endogenous-tau-into-the-somatodendritic-compartment-and-axonal-transport-dysfunction
#8
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/28473749/amyloid-%C3%AE-exposed-human-astrocytes-overproduce-phospho-tau-and-overrelease-it-within-exosomes-effects-suppressed-by-calcilytic-nps-2143-further-implications-for-alzheimer-s-therapy
#9
Anna Chiarini, Ubaldo Armato, Emanuela Gardenal, Li Gui, Ilaria Dal Prà
The two main drivers of Alzheimer's disease (AD), amyloid-β (Aβ) and hyperphosphorylated Tau (p-Tau) oligomers, cooperatively accelerate AD progression, but a hot debate is still ongoing about which of the two appears first. Here we present preliminary evidence showing that Tau and p-Tau are expressed by untransformed cortical adult human astrocytes in culture and that exposure of such cells to an Aβ42 proxy, Aβ25-35, which binds the calcium-sensing receptor (CaSR) and activates its signaling, significantly increases intracellular p-Tau levels, an effect CaSR antagonist (calcilytic) NPS 2143 wholly hinders...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28472993/humanized-monoclonal-antibody-armanezumab-specific-to-n-terminus-of-pathological-tau-characterization-and-therapeutic-potency
#10
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/28458925/pathological-role-of-peptidyl-prolyl-isomerase-pin1-in-the-disruption-of-synaptic-plasticity-in-alzheimer-s-disease
#11
Lingyan Xu, Zhiyun Ren, Frances E Chow, Richard Tsai, Tongzheng Liu, Flavio Rizzolio, Silvia Boffo, Yungen Xu, Shaohui Huang, Carol F Lippa, Yuesong Gong
Synaptic loss is the structural basis for memory impairment in Alzheimer's disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28456942/synaptic-dysfunction-in-alzheimer-s-disease-a%C3%AE-tau-and-epigenetic-alterations
#12
Ke Li, Qing Wei, Fang-Fang Liu, Fan Hu, Ao-Ji Xie, Ling-Qiang Zhu, Dan Liu
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized in the early stages by loss of learning and memory. However, the mechanism underlying these symptoms remains unclear. The best correlation between cognitive decline and pathological changes is in synaptic dysfunction. Histopathological hallmarks of AD are the abnormal aggregation of Aβ and Tau. Evidence suggests that Aβ and Tau oligomers contribute to synaptic loss in AD. Recently, direct links between epigenetic alterations, such as dysfunction in non-coding RNAs (ncRNAs), and synaptic pathologies have emerged, raising interest in exploring the potential roles of ncRNAs in the synaptic deficits in AD...
April 29, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28453485/tau-oligomers-in-sera-of-patients-with-alzheimer-s-disease-and-aged-controls
#13
Michala Kolarova, Urmi Sengupta, Ales Bartos, Jan Ricny, Rakez Kayed
Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer's disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r = 0...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28438658/antioxidants-reduce-neurodegeneration-and-accumulation-of-pathologic-tau-proteins-in-the-auditory-system-after-blast-exposure
#14
Xiaoping Du, Matthew B West, Qunfeng Cai, Weihua Cheng, Donald L Ewert, Wei Li, Robert A Floyd, Richard D Kopke
Cochlear neurodegeneration commonly accompanies hair cell loss resulting from aging, ototoxicity, or exposures to intense noise or blast overpressures. However, the precise pathophysiological mechanisms that drive this degenerative response have not been fully elucidated. Our laboratory previously demonstrated that non-transgenic rats exposed to blast overpressures exhibited marked somatic accumulation of neurotoxic variants of the microtubule-associated protein, Tau, in the hippocampus. In the present study, we extended these analyses to examine neurodegeneration and pathologic Tau accumulation in the auditory system in response to blast exposure and evaluated the potential therapeutic efficacy of antioxidants on short-circuiting this pathological process...
April 22, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28426964/ipsc-derived-human-microglia-like-cells-to-study-neurological-diseases
#15
Edsel M Abud, Ricardo N Ramirez, Eric S Martinez, Luke M Healy, Cecilia H H Nguyen, Sean A Newman, Andriy V Yeromin, Vanessa M Scarfone, Samuel E Marsh, Cristhian Fimbres, Chad A Caraway, Gianna M Fote, Abdullah M Madany, Anshu Agrawal, Rakez Kayed, Karen H Gylys, Michael D Cahalan, Brian J Cummings, Jack P Antel, Ali Mortazavi, Monica J Carson, Wayne W Poon, Mathew Blurton-Jones
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates...
April 19, 2017: Neuron
https://www.readbyqxmd.com/read/28421539/%C3%AE-synuclein-aggregates-with-%C3%AE-amyloid-or-tau-in-human-red-blood-cells-correlation-with-antioxidant-capability-and-physical-exercise-in-human-healthy-subjects
#16
Simona Daniele, Deborah Pietrobono, Jonathan Fusi, Caterina Iofrida, Lucia Chico, Lucia Petrozzi, Annalisa Lo Gerfo, Filippo Baldacci, Fabio Galetta, Gabriele Siciliano, Ubaldo Bonuccelli, Gino Santoro, Maria Letizia Trincavelli, Ferdinando Franzoni, Claudia Martini
Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid1-42 (Aβ), and tau, in both brain and peripheral tissue. In addition to homo-oligomers, the role of α-syn interactions with Aβ or tau has gradually emerged. The altered protein accumulation has been related to both oxidative stress and physical activity; nevertheless, no correlation among the presence of peripheral α-syn hetero-aggregates, antioxidant capacity, and physical exercise has been discovered as of yet...
April 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28420982/tau-oligomers-cytotoxicity-propagation-and-mitochondrial-damage
#17
REVIEW
Scott S Shafiei, Marcos J Guerrero-Muñoz, Diana L Castillo-Carranza
Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28420443/tau-phosphorylation-induced-by-severe-closed-head-traumatic-brain-injury-is-linked-to-the-cellular-prion-protein
#18
Richard Rubenstein, Binggong Chang, Natalia Grinkina, Eleanor Drummond, Peter Davies, Meir Ruditzky, Deep Sharma, Kevin Wang, Thomas Wisniewski
Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-β oligomers (Aβo). This PrP(C)-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Aβo production but upstream of intracellular toxicity within neurons...
April 18, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28392295/oleocanthal-ameliorates-amyloid-%C3%AE-oligomers-toxicity-on-astrocytes-and-neuronal-cells-in-vitro-studies
#19
Yazan S Batarseh, Loqman A Mohamed, Sweilem B Al Rihani, Youssef M Mousa, Abu Bakar Siddique, Khalid A El Sayed, Amal Kaddoumi
Extra-virgin olive oil (EVOO) has several health promoting effects. Evidence have shown that EVOO attenuates the pathology of amyloid-β (Aβ) and improves cognitive function in experimental animal models, suggesting it's potential to protect and reduce the risk of developing Alzheimer's disease (AD). Available studies have linked this beneficial effect to oleocanthal, one of the active components in EVOO. The effect of oleocanthal against AD pathology has been linked to its ability to attenuate Aβ and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild-type and AD transgenic mice in vivo...
June 3, 2017: Neuroscience
https://www.readbyqxmd.com/read/28382304/tau-oligomers-in-cerebrospinal-fluid-in-alzheimer-s-disease
#20
Urmi Sengupta, Erik Portelius, Oskar Hansson, Kathleen Farmer, Diana Castillo-Carranza, Randall Woltjer, Henrik Zetterberg, Douglas Galasko, Kaj Blennow, Rakez Kayed
OBJECTIVE: With an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD. METHODS: A multicentric collaborative study involving a double-blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed...
April 2017: Annals of Clinical and Translational Neurology
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