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Tau oligomers

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https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28790888/amyloid-%C3%AE-1-42-a%C3%AE-1-42-induces-the-cdk2-mediated-phosphorylation-of-tau-through-the-activation-of-the-mtorc1-signaling-pathway-while-promoting-neuronal-cell-death
#10
Ki Hoon Lee, Sei-Jung Lee, Hyun Jik Lee, Gee Euhn Choi, Young Hyun Jung, Dah Ihm Kim, Amr Ahmed Gabr, Jung Min Ryu, Ho Jae Han
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid β1-42 (Aβ) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aβ induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aβ with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28760161/mutation-induced-loss-of-app-function-causes-gabaergic-depletion-in-recessive-familial-alzheimer-s-disease-analysis-of-osaka-mutation-knockin-mice
#11
Tomohiro Umeda, Tetsuya Kimura, Kayo Yoshida, Keizo Takao, Yuki Fujita, Shogo Matsuyama, Ayumi Sakai, Minato Yamashita, Yuki Yamashita, Kiyouhisa Ohnishi, Mamiko Suzuki, Hiroshi Takuma, Tsuyoshi Miyakawa, Akihiko Takashima, Takashi Morita, Hiroshi Mori, Takami Tomiyama
The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity...
July 31, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28758136/a-mouse-model-of-focal-vascular-injury-induces-astrocyte-reactivity-tau-oligomers-and-aberrant-behavior
#12
Aric F Logsdon, Brandon P Lucke-Wold, Ryan C Turner, Xinlan Li, Chris E Adkins, Afroz S Mohammad, Jason D Huber, Charles L Rosen, Paul R Lockman
Neuropsychiatric symptom development has become more prevalent with 270,000 blast exposures occurring in the past 10 years in the United States. How blast injury leads to neuropsychiatric symptomology is currently unknown. Preclinical models of blast-induced traumatic brain injury have been used to demonstrate blood-brain barrier disruption, degenerative pathophysiology, and behavioral deficits. Vascular injury is a primary effect of neurotrauma that can trigger secondary injury cascades and neurodegeneration...
April 2017: Archives of Neuroscience
https://www.readbyqxmd.com/read/28709498/targeting-fyn-kinase-in-alzheimer-s-disease
#13
REVIEW
Haakon B Nygaard
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD...
June 13, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28699522/targeting-human-astrocytes-calcium-sensing-receptors-for-treatment-of-alzheimer-s-disease
#14
Anna Chiarini, Ubaldo Armato, James F Whitfield, Ilaria Dal Pra
Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein (APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase cleaving engendering AD-driving Aβ42/Aβ42-os peptides...
July 10, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28696431/synaptic-activity-protects-against-ad-and-ftd-like-pathology-via-autophagic-lysosomal-degradation
#15
Y Akwa, E Gondard, A Mann, E Capetillo-Zarate, E Alberdi, C Matute, S Marty, T Vaccari, A M Lozano, E E Baulieu, D Tampellini
Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein...
July 11, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28696204/ltp-and-memory-impairment-caused-by-extracellular-a%C3%AE-and-tau-oligomers-is-app-dependent
#16
Daniela Puzzo, Roberto Piacentini, Mauro Fá, Walter Gulisano, Domenica D Li Puma, Agnes Staniszewski, Hong Zhang, Maria Rosaria Tropea, Sara Cocco, Agostino Palmeri, Paul Fraser, Luciano D'Adamio, Claudio Grassi, Ottavio Arancio
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP...
July 11, 2017: ELife
https://www.readbyqxmd.com/read/28671129/dual-mechanism-of-toxicity-for-extracellular-injection-of-tau-oligomers-versus-monomers-in-human-tau-mice
#17
Giusi Manassero, Michela Guglielmotto, Debora Monteleone, Valeria Vasciaveo, Olena Butenko, Elena Tamagno, Ottavio Arancio, Massimo Tabaton
The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28670737/a-human-scfv-antibody-that-targets-and-neutralizes-high-molecular-weight-pathogenic-amyloid-%C3%AE-oligomers
#18
Adriano Sebollela, Erika N Cline, Izolda Popova, Kevin Luo, Xiaoxia Sun, Jay Ahn, Milena A Barcelos, Vanessa N Bezerra, Natalia M Lyra E Silva, Jason Patel, Nathalia R Pinheiro, Lei A Qin, Josette M Kamel, Anthea Weng, Nadia DiNunno, Adrian M Bebenek, Pauline T Velasco, Kirsten L Viola, Pascale N Lacor, Sergio T Ferreira, William L Klein
Brain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of AβO species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher-order oligomers. However, there is no consensus in the literature regarding which AβO species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of AβOs would be a valuable asset in the identification, isolation, and characterization of AD-relevant AβO species...
July 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28655349/oligomeric-tau-targeted-immunotherapy-in-tg4510-mice
#19
Sulana Schroeder, Aurelie Joly-Amado, Ahlam Soliman, Urmi Sengupta, Rakiz Kayed, Marcia N Gordon, David Morgan
BACKGROUND: Finding ways to reverse or prevent the consequences of pathogenic tau in the brain is of considerable importance for treatment of Alzheimer's disease and other tauopathies. Immunotherapy against tau has shown promise in several mouse models. In particular, an antibody with selectivity for oligomeric forms of tau, tau oligomer monoclonal antibody (TOMA), has shown rescue of the behavioral phenotype in several murine models of tau deposition. METHODS: In this study, we examined the capacity of TOMA to rescue the behavioral, histological, and neurochemical consequences of tau deposition in the aggressive Tg4510 model...
June 27, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28654636/human-cyclophilin-40-unravels-neurotoxic-amyloids
#20
Jeremy D Baker, Lindsey B Shelton, Dali Zheng, Filippo Favretto, Bryce A Nordhues, April Darling, Leia E Sullivan, Zheying Sun, Parth K Solanki, Mackenzie D Martin, Amirthaa Suntharalingam, Jonathan J Sabbagh, Stefan Becker, Eckhard Mandelkow, Vladimir N Uversky, Markus Zweckstetter, Chad A Dickey, John Koren, Laura J Blair
The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases)...
June 2017: PLoS Biology
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