Are Tangles as Toxic as They Look?

Spires‐Jones, Tara L.; Kopeikina, Katherine J.; Koffie, Robert M.; Calignon, Alix de; Hyman, Bradley T.

doi:10.1007/s12031-011-9566-7

Cited by 96 publications

(83 citation statements)

References 64 publications

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“…FKBP51 overexpression enhanced neuronal loss in the rTg4510 tau transgenic mouse model, suggesting that FKBP51 coordinates with Hsp90 to prevent tau clearance and facilitate its toxicity. This provides further evidence that other forms of tau, besides those that are pathologically visible in postmortem tissue like tangles, are highly neurotoxic (5,45,55,56). Thus, factors that facilitate FKBP51 expression could promote an environment in the aging brain that supports tau pathogenesis.…”

Section: Discussionmentioning

confidence: 72%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

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Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5 -/-mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

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Section: Discussionmentioning

confidence: 72%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

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“…1O-Q) revealed the presence of AT8-positive hyperphosphorylated tau and T22-positive tau oligomers present in adjacent cells. Western blot of Htau mice of different ages (6,(11)(12), and 22 months) with Tau-5 and TOMA revealed an increase in higher molecular weight oligomeric tau species with age, while no tau was detected in tau KO mice ( Fig. 2A-B).…”

Section: Htau Mice Show Increased Tau Oligomer Levels With Agementioning

confidence: 94%

“…Moreover, in AD, hippocampal neurons can survive for up to 20 years with NFTs [6]. Additionally, in animal models, disease phenotypes are not associated with NFT levels [7][8][9][10][11][12][13][14][15], including in mice overexpressing human tau (Htau mice) [16,17]. Therefore, it seems likely that intermediate species may underlie toxicity.…”

Section: Introductionmentioning

confidence: 99%

Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

Castillo-Carranza

Gerson

Sengupta

et al. 2014

JAD

147

128

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Abstract. Neurodegenerative disease is one of the greatest health crises in the world and as life expectancy rises, the number of people affected will continue to increase. The most common neurodegenerative disease, Alzheimer's disease, is a tauopathy, characterized by the presence of aggregated tau, namely in the form of neurofibrillary tangles. Historically, neurofibrillary tangles have been considered the main tau species of interest in Alzheimer's disease; however, we and others have shown that tau oligomers may be the most toxic form and the species responsible for the spread of pathology. We developed a novel anti-tau oligomer-specific mouse monoclonal antibody (TOMA) and investigated the potential of anti-tau oligomer passive immunization in preventing the toxicity of tau pathology in Htau mice. We injected pure brain-derived tau oligomers intracerebrally in 3-monthold wild-type and Htau mice and investigated the protective effects of a single 60 g TOMA injection when compared to the same dose of non-specific IgG and found that TOMA conferred protection against the accumulation of tau oligomers and cognitive deficits for up to 1 month after treatment. Additionally, we injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and treated animals with biweekly injections of 60 g TOMA or non-specific IgG. We found that long-term administration of TOMA was effective as a preventative therapy, inhibiting oligomeric tau and preserving memory function. These results support the critical role of oligomeric tau in disease progression and validate tau oligomers as a potential drug target.

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“…2). Recent experimental evidence indicates that soluble oligomeric tau isoforms represent the toxic species [26][27][28]. In contrast, the deposition of higher-order tau aggregates within NFTs may be a cellular response aimed at reducing this toxicity [27,29].…”

Section: Tau Hyperphosphorylation and Its Relation To Admentioning

confidence: 99%

“…Recent experimental evidence indicates that soluble oligomeric tau isoforms represent the toxic species [26][27][28]. In contrast, the deposition of higher-order tau aggregates within NFTs may be a cellular response aimed at reducing this toxicity [27,29]. This is reminiscent of the situation in amyloid plaques, where the Aß fragments seem to exert their toxic effects more efficiently in the form of soluble oligomeric precursors, rather than in the aggregates found in the amyloid plaques (reviewed in [3,30]).…”

Section: Tau Hyperphosphorylation and Its Relation To Admentioning

confidence: 99%

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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Are Tangles as Toxic as They Look?

Cited by 96 publications

References 64 publications

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

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

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