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Sang-Won Min, Peter Dongmin Sohn, Yaqiao Li, Nino Devidze, Jeffrey R Johnson, Nevan J Krogan, Eliezer Masliah, Sue-Ann Mok, Jason E Gestwicki, Li Gan
Hyperacetylation of tau has been implicated in neurodegeneration and cognitive decline in tauopathy brains. The NAD-dependent class III protein deacetylase SIRT1 is one of major enzymes involved in removal of acetyl groups from tau in vitro However, whether SIRT1 regulates acetylation of pathogenic tau and ameliorates tau-mediated pathogenesis remains unclear. Here, we report deacetylating activity of SIRT1 for acetylated Lys174 (K174) of tau in tauP301S transgenic mice with a brain-specific SIRT1 deletion...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Mar Pérez, Miguel Medina, Félix Hernández, Jesús Avila
The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasing evidence in recent years supports the notion that Tau pathology spreading throughout the brain in AD and other Tauopathies is the consequence of the propagation of specific Tau species along neuroanatomically connected brain regions in a so-called "prion-like" manner. A number of steps are assumed to be involved in this process, including secretion, cellular uptake, transcellular transfer and/or seeding, although the precise mechanisms underlying propagation of Tau pathology are not fully understood yet...
March 5, 2018: Biomolecular Concepts
Itsuki Hasegawa, Akitoshi Takeda, Hiroyuki Hatsuta, Yuki Kubo, Masahiko Ohsawa, Yuta Nakano, Takeshi Ikeuchi, Masato Hasegawa, Shigeo Murayama, Yoshiaki Itoh
Globular glial tauopathy (GGT) is a 4-repeat (4R) tauopathy in which 4R tau accumulates to form globular glial inclusions (GGIs), predominantly in oligodendroglia. To date, little has been reported on iron deposits in patients with GGT. We report a case of GGT with iron deposits in a 78-year-old woman presenting with an 8-year history of slowly progressing limb weakness and cognitive decline. Susceptibility-weighted imaging revealed a low signal intensity in the right precentral gyrus, suggesting iron deposition...
March 6, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
A Borreca, V Latina, V Corsetti, S Middei, S Piccinin, F Della Valle, R Bussani, M Ammassari-Teule, R Nisticò, P Calissano, G Amadoro
The NH2 tau 26-44 aa (i.e., NH2 htau) is the minimal biologically active moiety of longer 20-22-kDa NH2 -truncated form of human tau-a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)-which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated...
March 5, 2018: Molecular Neurobiology
Alice Bittar, Urmi Sengupta, Rakez Kayed
With increasing age, as the incidence of Alzheimer's disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer's disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding a successful clinical therapy has been a great challenge, possibly indicating a lack of accuracy in targeting the toxic species...
2018: NPJ Vaccines
Alessandra Maria Calogero, Mariele Viganò, Silvia Budelli, Daniela Galimberti, Chiara Fenoglio, Daniele Cartelli, Lorenza Lazzari, Petri Lehenkari, Margherita Canesi, Rosaria Giordano, Graziella Cappelletti, Gianni Pezzoli
Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease whose etiopathogenesis remains elusive. The intraneuronal accumulation of hyperphosphorylated Tau, a pivotal protein in regulating microtubules (MT), leads to include PSP into tauopathies. Pathological hallmarks are well known in neural cells but no word yet if PSP-linked dysfunctions occur also in other cell types. We focused on bone marrow mesenchymal stromal cells (MSCs) that have recently gained attention for therapeutic interventions due to their anti-inflammatory, antiapoptotic and trophic properties...
March 4, 2018: Journal of Cellular and Molecular Medicine
Hiroyuki Honda, Naokazu Sasagasako, Chang Shen, Masahiro Shijo, Hideomi Hamasaki, Satoshi O Suzuki, Yoshio Tsuboi, Naoki Fujii, Toru Iwaki
INTRODUCTION: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. METHODS: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance...
February 23, 2018: Parkinsonism & related Disorders
Sara E Nasrabady, Batool Rizvi, James E Goldman, Adam M Brickman
Alzheimer's disease (AD) is conceptualized as a progressive consequence of two hallmark pathological changes in grey matter: extracellular amyloid plaques and neurofibrillary tangles. However, over the past several years, neuroimaging studies have implicated micro- and macrostructural abnormalities in white matter in the risk and progression of AD, suggesting that in addition to the neuronal pathology characteristic of the disease, white matter degeneration and demyelination may be also important pathophysiological features...
March 2, 2018: Acta Neuropathologica Communications
Cristina Lois, Ivan Gonzalez, Keith A Johnson, Julie C Price
The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-[Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B (11 C-PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline...
March 1, 2018: Brain Imaging and Behavior
F Ali, J L Whitwell, P R Martin, M L Senjem, D S Knopman, C R Jack, V J Lowe, R C Petersen, B F Boeve, K A Josephs
Corticobasal syndrome (CBS) is a phenotypic manifestation of diverse pathologies, including Alzheimer's disease and 4-repeat tauopathies. Predicting pathology in CBS is unreliable and, hence, molecular neuroimaging may prove to be useful. The aim of this study was to assess regional patterns of uptake on [18 F] AV-1451 PET in CBS and determine whether patterns of uptake differ according to beta-amyloid deposition or differing clinical presentations. Fourteen patients meeting criteria for CBS underwent Pittsburgh Compound B (PiB) and [18 F] AV-1451 PET...
March 1, 2018: Journal of Neurology
Michel Goedert, Yoshiki Yamaguchi, Sushil K Mishra, Makoto Higuchi, Naruhiko Sahara
A pathological pathway leading from soluble, monomeric to insoluble, filamentous Tau, is believed to underlie human Tauopathies. Cases of frontotemporal dementia are caused by dominantly inherited mutations in MAPT , the Tau gene. They show that dysfunction of Tau protein is sufficient to cause neurodegeneration and dementia. Extrapolation to the more common sporadic Tauopathies leads one to conclude that the pathological pathway is central to the development of all cases of disease, even if there are multiple reasons for Tau assembly...
2018: Frontiers in Neurology
Almudena Fuster-Matanzo, Félix Hernández, Jesús Ávila
Tauopathies comprise a group of progressive age-associated neurodegenerative diseases where tau protein deposits are found as the predominant pathological signature (primary tauopathies) or in combination with the presence of other toxic aggregates (secondary tauopathies). In recent years, emerging evidence suggests that abnormal tau accumulation is mediated through spreading of seeds of the protein from cell to cell, favouring the hypothesis of a prion-like transmission of tau to explain the propagation of the pathology...
February 25, 2018: International Journal of Molecular Sciences
Khalid Iqbal, Fei Liu, Cheng-Xin Gong
Alzheimer's disease (AD), which accounts for three fourth of all cases of dementia, is a major public health problem in modern society and, yet, there is no effective treatment available that can prevent or inhibit this chronic progressive neurodegenerative disease. A major current drug target is intraneuronal abnormally hyperphosphorylated microtubule-associated protein tau which is a histopathological hallmark of this disease and of a family of neurodegenerative diseases called tauopathies. Areas covered: In this review, the authors discuss a growing number of studies that describe the nature and mechanism of tau pathology and various drug discovery options and most recent developments in tau-based therapeutics...
March 1, 2018: Expert Opinion on Drug Discovery
Sarah E Scullion, Gareth R I Barker, E Clea Warburton, Andrew D Randall, Jonathan T Brown
Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L . We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory...
February 26, 2018: Neurochemical Research
Peter Verwilst, Hyeong Seok Kim, Soobin Kim, Chulhun Kang, Jong Seung Kim
Historically, in Alzheimer's disease research, a lot of attention has been paid to the development of highly selective fluorophores for beta amyloid plaques. With a shift in the understanding of the disease and the importance of a network of cross-talk interactions, the development of small-molecule fluorescent dyes with high selectivity for (hyperphosphorylated) tau protein aggregates in neurofibrillary tangles has been gaining increasing attention. Fluorescent dyes for the selective labelling of tau aggregates in histological AD brain sections have been described, spanning the entire visible range of the electromagnetic spectrum...
February 27, 2018: Chemical Society Reviews
Yan Zhou, Jianhua Shi, Dandan Chu, Wen Hu, Zongyu Guan, Cheng-Xin Gong, Khalid Iqbal, Fei Liu
Microtubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer's disease (AD) and related tauopathies. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain are not very clear. In the present study we investigated the association of phosphorylation and truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by western blots...
2018: Frontiers in Aging Neuroscience
Taeko Kimura, Govinda Sharma, Koichi Ishiguro, Shin-Ichi Hisanaga
Tau is a microtubule-associated protein which regulates the assembly and stability of microtubules in the axons of neurons. Tau is also a major component of neurofibrillary tangles (NFTs), a pathological hallmark in Alzheimer's disease (AD). A characteristic of AD tau is hyperphosphorylation with more than 40 phosphorylation sites. Aggregates of hyperphosphorylated tau are also found in other neurodegenerative diseases which are collectively called tauopathies. Although a large number of studies have been performed on the phosphorylation of AD tau, it is not known if there is disease-specific phosphorylation among tauopathies...
2018: Frontiers in Neuroscience
Yanping Zhu, Xiaoyang Shan, Farzaneh Safarpour, Nancy Erro Go, Nancy Li, Alice Shan, Mina Huang, Matthew Deen, Viktor Holicek, Roger Ashmus, Zarina Madden, Sharon Gorski, Michael Silverman, David J Vocadlo
The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer Disease (AD) mouse models manifesting either tau or amyloid pathology...
February 20, 2018: ACS Chemical Neuroscience
Brent Race, Katie Williams, Andrew G Hughson, Casper Jansen, Piero Parchi, Annemieke J M Rozemuller, Bruce Chesebro
Human familial prion diseases are associated with mutations at 34 different prion protein (PrP) amino acid residues. However, it is unclear whether infectious prions are found in all cases. Mutant PrP itself may be neurotoxic, or alternatively, PrP mutation might predispose to spontaneous formation of infectious PrP isoforms. Previous reports demonstrated transmission to animal models by human brain tissue expressing 7 different PrP mutations, but 3 other mutations were not transmissible. In the present work, we tested transmission using brain homogenates from patients expressing 3 untested PrP mutants: G131V, Y226X, and Q227X...
February 20, 2018: Acta Neuropathologica Communications
Maud Gratuze, Aurélie Joly-Amado, Didier Vieau, Luc Buée, David Blum
<br>Alzheimer's disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments and lower brain glucose metabolism, that often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood...
February 13, 2018: Neuroendocrinology
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