The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

Tai, Hwan‐Ching; Serrano-Pozo, Alberto; Hashimoto, Tadafumi; Frosch, Matthew P.; Spires‐Jones, Tara L.; Hyman, Bradley T.

doi:10.1016/j.ajpath.2012.06.033

Cited by 390 publications

(408 citation statements)

References 47 publications

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“…2 C and D) (20). Analysis of the LTP data revealed a significant CUS × Genotype interaction [F (1,27) = 6.283, P = 0.018] and overall effects of CUS [F (1,27) = 11.24, P = 0.002] and Genotype [F (1,27) = 41.35, P < 0.0001]. In addition, post hoc analysis revealed that LTP was reduced in slices from CUS-treated WT (P = 0.002), but not CUS-treated Tau-KO (P = 0.92), mice compared with their controls.…”

Section: Significancementioning

confidence: 99%

“…Tau hyperphosphorylation and missorting in dendrites and synapses are considered key mechanisms in the neuronal damage and atrophy that characterize AD (24)(25)(26)(27). In light of the above evidence that Tau is required for the manifestation of CUS-induced neuronal atrophy and dysfunction (Figs.…”

Section: Chronic Stress Evokes Tau Hyperphosphorylation and Missortinmentioning

confidence: 99%

“…were subject to CUS × Genotype interactions [F (1,27) 25 ms = 7.100, P = 0.012; F (1,27) 50 ms = 9.148, P = 0.005], and Genotype had an overall effect on this parameter [F (1,27) 25 ms = 4.777, P = 0.037; F (1,27) 50 ms = 5.034, P = 0.033]. Post hoc analysis revealed that CUS decreases the probability of synaptic release in slices of WT (p 50ms = 0.02), but not Tau-KO (p 50ms = 0.66), mice ( Fig. 2 E and F).…”

Section: Significancementioning

confidence: 99%

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Tau protein is essential for stress-induced brain pathology

Lopes

Vaz‐Silva

Pinto

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

126

111

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Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer's-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function.Tau | stress | hippocampus | depression | memory deficits T he cytoskeletal protein Tau is implicated in the establishment of Alzheimer's disease (AD) (1) as well as excitotoxicity (1) and, more recently, epilepsy (2, 3). Exposure to stressful conditions induces depressive behavior and memory deficits in both rodents and humans (4-8). Studies in rodents have shown that chronic stress triggers Tau hyperphosphorylation, a key pathogenic mechanism in AD, and results in cognitive and mood deficits (9-13); however, those studies do not provide direct evidence for a role of Tau in stress-evoked brain pathology. Given that Tau plays an important role in regulating neuronal architecture and function through its interaction with various cellular targets (e.g., tubulin and Fyn) (14), we hypothesized that Tau mediates the deleterious actions of stress on brain structure and function.To test the above hypothesis, we compared the impact of chronic unpredictable stress (CUS) (11, 15) in mice carrying a null mutation of the mapt gene [Tau knockout (Tau-KO) mice] (16) with their wild-type (WT) littermates. Three well-characterized behavioral endpoints (cognition, coping styles, and anxiety) that are disrupted by CUS served as the primary assay endpoints; these were complemented with measures of hippocampal structural and functional integrity. The hippocampus is a central component of the neurocircuitries that control these behaviors and displays overt lesions in both stress-and Tau-related pathologies; in the latter, the hippocampus is one of the earliest brain regions to show signs of neurodegeneration (1,4,7,(10)(11)(12)(13)17). ResultsDeleterious Effects of Stress on Memory and Mood Are Abrogated in the Absence of Tau Protein. Cognition, mood, and anxiety are interdependent behavioral domains that exhibit complex interactions (5). Different forms of memory were assessed after exposure of WT and Tau-KO mice to the CUS paradigm; the test battery included the Y-maze, Morris water maze (MWM), and the novel object recognition test (NOR). Anxiety was evaluated using the elevated plus maze (EPM), and coping styles and anhedonia were assessed using the forced swim test (FST) and the sucrose consumption test (SCT).Two-way ANOVA ...

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Section: Significancementioning

confidence: 99%

Section: Chronic Stress Evokes Tau Hyperphosphorylation and Missortinmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Tau protein is essential for stress-induced brain pathology

Lopes

Vaz‐Silva

Pinto

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

126

111

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“…New findings on the role of tau protein have been described by Tai et al [23], who demonstrated that, in addition to its well-described axonal localization, tau is present at both presynaptic and postsynaptic terminals in normal human brains. In AD, tau becomes hyperphosphorylated and misfolded at both terminals, and the accumulation of hyperphosphorylated oligomers at synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system.…”

Section: Research Aspectsmentioning

confidence: 98%

Progress in Alzheimer’s disease research in the last year

Galimberti

Scarpini

2013

J Neurol

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Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with a prevalence of 5 % after 65 years of age, increasing to about 30 % in people aged 85 years or older. It is characterized by progressive cognitive impairment, including impaired judgment, decision-making and orientation, and in some cases accompanied by psycho behavioral disturbances or language impairment. Herein, we summarize and discuss the main articles describing novel findings in AD published over the last year, including clinical, therapeutic, and research issues.

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“…Thus, synaptic accumulation of hyperphosphorylated tau was observed in cells with a defective ubiquitin/proteasome system [53]. Since ubiquitinated tau is mainly found in the insoluble NFTs which accumulate late in AD rather than in the soluble oligomers, ubiquitination may be a way of detoxification.…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 98%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

Cited by 390 publications

References 47 publications

Tau protein is essential for stress-induced brain pathology

Tau protein is essential for stress-induced brain pathology

Progress in Alzheimer’s disease research in the last year

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

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