Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

Rissman, Robert A.; Poon, Wayne W.; Blurton‐Jones, Mathew; Oddo, Salvatore; Torp, Reidun; Vitek, Michael P.; LaFerla, Frank M.; Rohn, Troy T.; Cotman, Carl W.

doi:10.1172/jci200420640

Cited by 415 publications

(357 citation statements)

References 81 publications

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“…In addition, the caspase-3 cleaved tau fragment exerted toxic effects in tissue-culture experiments. [187][188][189] Caspase-3 is activated in AD, and PHFs from AD-brains were recognized by antibodies directed against the caspase-3 cleavage site of tau. 150,187,188 The caspase-3 specific inhibitor AcDEVD-CHO inhibited tau cleavage and reduced A␤-mediated toxicity in organotypic rat brain slices.…”

Section: Tau Clearancementioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Section: Tau Clearancementioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…Tau contains many potential cleavage sites accessible to multiple proteases, yielding breakdown products that could be toxic in various ways. For example, cleavage of the tails by caspases (behind D421 or behind D13; Gamblin et al 2003;Horowitz et al 2004;Rissman et al 2004) perturbs the paperclip folding of Tau (Jeganathan et al 2006) and makes it more vulnerable to aggregation. Tau can be cleaved by calpain at a number of sites (Canu and Calissano 2003;Park and Ferreira 2005).…”

mentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

705

636

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Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications ( phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming b structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.

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“…It is widely believed that δTau facilitates Tau aggregation into insoluble forms and the formation of NFTs. 20,21,[31][32][33] Hence, caspase-mediated Tau cleavage is viewed as an early pathological event triggering NFT pathology and δTau as a critical toxic moiety underlying neurodegeneration. 21,31,34,35 However, the data supporting a pathogenic role of δTau are correlative and/or based on aberrant overexpression of Tau and δTau.…”

Section: Introductionmentioning

confidence: 99%

“…20,21,[31][32][33] Hence, caspase-mediated Tau cleavage is viewed as an early pathological event triggering NFT pathology and δTau as a critical toxic moiety underlying neurodegeneration. 21,31,34,35 However, the data supporting a pathogenic role of δTau are correlative and/or based on aberrant overexpression of Tau and δTau. 34,36,37 Thus, the possibility that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic forms of Tau and/or to generate 'beneficial' Tau fragments must still be considered.…”

Section: Introductionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology

Cited by 415 publications

References 81 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

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