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Tau oligomers

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https://www.readbyqxmd.com/read/29137322/the-c-jun-n-terminal-kinase-plays-a-key-role-in-ocular-degenerative-changes-in-a-mouse-model-of-alzheimer-disease-suggesting-a-correlation-between-ocular-and-brain-pathologies
#1
Lucia Buccarello, Alessandra Sclip, Matteo Sacchi, Anna Maria Castaldo, Ilaria Bertani, Andrea ReCecconi, Silvia Maestroni, Gianpaolo Zerbini, Paolo Nucci, Tiziana Borsello
Recently a range of ocular manifestations such as retinal and lens amyloid-beta accumulation and retinal nerve fiber layer loss have been proposed as potential biomarkers in Alzheimer disease (AD). The TgCRND8 mouse model of AD exhibits age-dependent amyloid β (Aβ) oligomers accumulation and cognitive defects, amyloid plaques and hyperphosphorylated Tau deposition and inflammation. We proved the correlation between ocular pathologies and AD, observing increased levels of p-APP and p-Tau, accumulation of Aβ oligomers in the retina, eye, and optic nerve...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29118388/near-infrared-light-decreases-synaptic-vulnerability-to-amyloid-beta-oligomers
#2
Michele M Comerota, Balaji Krishnan, Giulio Taglialatela
Synaptic dysfunction due to the disrupting binding of amyloid beta (Aβ) and tau oligomers is one of the earliest impairments in Alzheimer's Disease (AD), driving initial cognitive deficits and clinical manifestation. Consequently, there is ample consensus that preventing early synaptic dysfunction would be an effective therapeutic strategy for AD. With this goal in mind, we investigated the effect of a treatment of mice with near infrared (NIR) light on synaptic vulnerability to Aβ oligomers. We found that Aβ oligomer binding to CNS synaptosomes isolated from wild type (wt) mice treated with NIR light was significantly reduced and the resulting suppression of long term potentiation (LTP) by Aβ oligomers was prevented...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29103036/the-unexpected-role-of-a%C3%AE-1-42-monomers-in-the-pathogenesis-of-alzheimer-s-disease
#3
Elena Tamagno, Michela Guglielmotto, Debora Monteleone, Giusi Manassero, Valeria Vasciaveo, Massimo Tabaton
Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation...
October 30, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29063514/biomarkers-of-neuronal-injury-and-amyloid-metabolism-in-the-cerebrospinal-fluid-of-patients-infected-with-hiv-1-subtypes-b-and-c
#4
Sérgio Monteiro de Almeida, Clea E Ribeiro, Indianara Rotta, Mauro Piovesan, Bin Tang, Florin Vaida, Sonia Mara Raboni, Scott Letendre, Michael Potter, Meire S Batistela Fernandes, Ronald J Ellis
Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau181), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression...
October 23, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/29053786/tau-hyperphosphorylation-induces-oligomeric-insulin-accumulation-and-insulin-resistance-in-neurons
#5
Patricia Rodriguez-Rodriguez, Anna Sandebring-Matton, Paula Merino-Serrais, Cristina Parrado-Fernandez, Alberto Rabano, Bengt Winblad, Jesús Ávila, Isidre Ferrer, Angel Cedazo-Minguez
Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression...
October 13, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29021554/human-tau-p301l-overexpression-results-in-tau-hyperphosphorylation-without-neurofibrillary-tangles-in-adult-zebrafish-brain
#6
Mehmet I Cosacak, Prabesh Bhattarai, Ledio Bocova, Tim Dzewas, Violeta Mashkaryan, Christos Papadimitriou, Kerstin Brandt, Heike Hollak, Christopher L Antos, Caghan Kizil
Microtubule-associated TAU protein is a pathological hallmark in Alzheimer's disease (AD), where hyperphosphorylation of TAU generates neurofibrillary tangles. To investigate the effects of TAU in a regenerative adult vertebrate brain system, we generated a cre/lox-based transgenic model of zebrafish that chronically expresses human TAU(P301L), which is a variant of human TAU protein that forms neurofibrillary tangles in mouse models and humans. Interestingly, we found that although chronic and abundant expression of TAU(P301L) starting from early embryonic development led to hyperphosphorylation, TAU(P301L) did not form oligomers and neurofibrillary tangles, and did not cause elevated apoptosis and microglial activation, which are classical symptoms of tauopathies in mammals...
October 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28984591/curcumin-inhibits-tau-aggregation-and-disintegrates-preformed-tau-filaments-in-vitro
#7
Jitendra Subhash Rane, Prasenjit Bhaumik, Dulal Panda
The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28982375/pkr-involvement-in-alzheimer-s-disease
#8
REVIEW
Jacques Hugon, François Mouton-Liger, Julien Dumurgier, Claire Paquet
BACKGROUND: Brain lesions in Alzheimer's disease (AD) are characterized by Aβ accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, Aβ1-42 oligomers could trigger a neurotoxic cascade with kinase activation that leads to tau phosphorylation and neurodegeneration. Detrimental pathways that are associated with kinase activation could also be linked to the triggering of direct neuronal death, the production of free radicals, and neuroinflammation...
October 5, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28962864/blocking-sirt1-inhibits-cell-proliferation-and-promotes-aging-through-the-pi3k-akt-pathway
#9
Hongyan Li, Rong Wang
AIMS: Alzheimer's disease (AD) is the most prevalent age-related disease and the most common cause of dementia in the elderly. Its hallmark neuropathological features are the presence of amyloid-beta oligomers and neurofibrillary tangles that are composed of hyperphosphorylated tau protein. SIRT1 has been shown to have a neuroprotective effect; however, its working mechanisms are not well understood. This study aimed to address this issue. MAIN METHODS: We used an in vitro neuronal SH-SY5Y cell culture model to investigate the effect of SIRT1 knockdown on cell survival, proliferation, functionality, and cytotoxicity...
December 1, 2017: Life Sciences
https://www.readbyqxmd.com/read/28927263/molecular-and-cellular-basis-of-neurodegeneration-in-alzheimer-s-disease
#10
REVIEW
Sangyun Jeong
The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid β-peptide (Aβ) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than Aβ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD...
September 30, 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28924170/the-tyrosine-phosphatase-ptpn13-fap-1-links-calpain-2-tbi-and-tau-tyrosine-phosphorylation
#11
Yubin Wang, Randy A Hall, Moses Lee, Andysheh Kamgar-Parsi, Xiaoning Bi, Michel Baudry
Traumatic brain injury (TBI) increases the risk of Alzheimer's disease (AD). Calpain activation and tau hyperphosphorylation have been implicated in both TBI and AD. However, the link between calpain and tau phosphorylation has not been fully identified. We recently discovered that the two major calpain isoforms in the brain, calpain-1 and calpain-2, play opposite functions in synaptic plasticity and neuronal survival/death, which may be related to their different C-terminal PDZ binding motifs. Here, we identify the tyrosine phosphatase PTPN13 as a key PDZ binding partner of calpain-2...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#12
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28919235/alzheimer-s-disease-like-paired-helical-filament-assembly-from-truncated-tau-protein-is-independent-of-disulphide-cross-linking
#13
Youssra K Al-Hilaly, Saskia J Pollack, Devkee Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise C Serpell
Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process...
September 15, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28882311/production-of-recombinant-tau-oligomers-in-vitro
#14
Benjamin Combs, Chelsea T Tiernan, Chelsey Hamel, Nicholas M Kanaan
The pathological aggregation of the tau protein is a common characteristic of many neurodegenerative diseases. There is strong interest in characterizing the potentially toxic nature of tau oligomers. These nonfibrillar, soluble multimers appear to be more toxic than neurofibrillary tangles made up of filamentous tau. However, reliable production, purification, and verification of tau oligomers can provide certain challenges. Here, we provide a series of methods that address these issues. First, recombinant tau is produced using Escherichia coli, purified through affinity, size-exclusion, and anion-exchange chromatography steps and quantified using an SDS Lowry protein quantitation assay...
2017: Methods in Cell Biology
https://www.readbyqxmd.com/read/28874186/age-dependent-changes-in-synaptic-plasticity-enhance-tau-oligomerization-in-the-mouse-hippocampus
#15
Tetsuya Kimura, Mamiko Suzuki, Takumi Akagi
The aggregation mechanism of phosphorylated tau is an important therapeutic target for tauopathies, including Alzheimer's disease, although the mechanism by which aggregation occurs is still unknown. Because the phosphorylation process of tau is involved in the trafficking of AMPA receptors, which accompanies the long-term depression (LTD) of synapses, we examined the effect of LTD-inducing low-frequency stimulation (LFS) on the formation of pathological tau aggregates in adult and aged wild-type mice. Our biochemical analysis demonstrated that LFS led to the formation of sarkosyl-insoluble (SI) tau oligomers in aged hippocampi but not in adult hippocampi in wild-type mice...
September 6, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28841372/vitamin-b12-inhibits-tau-fibrillization-via-binding-to-cysteine-residues-of-tau
#16
Saharnaz Rafiee, Kazem Asadollahi, Gholamhossein Riazi, Shahin Ahmadian, Ali Akbar Saboury
Two mechanisms underlie the inhibitory/acceleratory action of chemical compounds on tau aggregation including the regulation of cellular kinases and phosphatases activity and direct binding to tau protein. Vitamin B12 is one of the tau polymerization inhibitors, and its deficiency is linked to inactivation of protein phosphatase 2A and subsequently hyperphosphorylation and aggregation of tau protein. Regarding the structure and function of vitamin B12 and tau protein, we assumed that vitamin B12 is also able to directly bind to tau protein...
September 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28837764/novel-cell-model-for-tauopathy-induced-by-a-cell-permeable-tau-related-peptide
#17
John R Veloria, Lin Li, Gail A M Breen, Warren J Goux
In the present study, a cell penetrating peptide (CPP)-amyloid conjugate was prepared (T-peptide), where the amyloid-forming sequence was homologous to a nucleating sequence from human Tau protein ((306)VQIVYK(311)). Kinetic and biophysical studies showed the peptide formed long-lived oligomers which were taken up by endocytosis and localized in perinuclear vesicles and in the cytoplasm of murine hippocampal neuroblastoma cells and human HeLa cells. Thioflavin S (ThS) staining of amyloid colocalized with pathological phosphorylated Tau, suggesting that the peptide was able to seed endogenous wild-type Tau...
September 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28835279/a%C3%AE-accumulation-causes-mvb-enlargement-and-is-modelled-by-dominant-negative-vps4a
#18
Katarina Willén, James R Edgar, Takafumi Hasegawa, Nobuyuki Tanaka, Clare E Futter, Gunnar K Gouras
BACKGROUND: Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. METHODS: MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy...
August 23, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28827321/hsp90-activator-aha1-drives-production-of-pathological-tau-aggregates
#19
Lindsey B Shelton, Jeremy D Baker, Dali Zheng, Leia E Sullivan, Parth K Solanki, Jack M Webster, Zheying Sun, Jonathan J Sabbagh, Bryce A Nordhues, John Koren, Suman Ghosh, Brian S J Blagg, Laura J Blair, Chad A Dickey
The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer's disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood-brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28821400/alzheimer-s-disease-as-oligomeropathy
#20
REVIEW
Kenjiro Ono
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by pathological aggregates of amyloid β-protein (Aβ) and tau protein. On the basis of genetic evidence, biochemical data, and animal models, Aβ has been suggested to be responsible for the pathogenesis of AD (the amyloid hypothesis). Aβ molecules tend to aggregate to form oligomers, protofibrils, and mature fibrils. Although mature fibrils in the final stage have been thought to be the cause of AD pathogenesis, recent studies using synthetic Aβ peptides, a cell culture model, Aβ precursor protein transgenic mice models, and human samples, such as cerebrospinal fluids and postmortem brains of AD patients, suggest that pre-fibrillar forms (oligomers of Aβ) are more deleterious than are extracellular fibril forms...
August 16, 2017: Neurochemistry International
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