Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Chung, Chin Hyun; Yu, Shi; Kim, Inki; Yoon, Won Joo; Ryu, Bo Rum; Jo, Dong Gyu; Woo, Ha-Na; Kwon, Yun Kyong; Kim, Hyun Hee; Gwag, Byoung Joo; Mook-Jung, In Hee; Jung, Yong Keun

doi:10.1006/nbdi.2000.0335

Cited by 192 publications

(177 citation statements)

References 62 publications

(53 reference statements)

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“…Increasing evidence suggests that caspases are activated in the AD brain (20)(21)(22)(23)(24)(25)(26). Furthermore, components of the neuronal cytoskeleton, including tau, are targeted by caspases following apoptotic stimuli (23,(27)(28)(29)(30)(31)(32)(33)(34). Although the role of tau caspase-cleavage in AD pathology remains unresolved, recent evidence now implicates the caspase-cleavage of tau in tangle pathology (34).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ 1-42 and is induced by Aβ 1-42 in vitro. Collectively, our data imply that Aβ accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…Studies from different 'in vitro' models of neuronal apoptosis as well as from AD samples suggest that proteases activated during apoptosis may cause tau truncation. It has been reported, for example, that tau is cleaved by caspase-3 in its C-terminal domain, [15][16][17] while studies on AD samples have reported that caspases cleave the N-terminal tau domain, 18 and that this event may precede the aggregation of tau into neurofibrillary tangles (NTF). Moreover, transfection of neuronal cells with C-terminal caspase-3 generated tau fragment 16,17 and with different fragments encompassing its C-terminal domain 17 induces cell death, suggesting that truncated forms of tau can operate as toxic agents of a selfpropagating intracellular process of neuronal death.…”

Section: Introductionmentioning

confidence: 99%

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

et al. 2003

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Although the role of the microtubule-binding domain of the tau protein in the modulation of microtubule assembly is widely established, other possible functions of this protein have been poorly investigated. We have analyzed the effect of adenovirally mediated expression of two fragments of the Nterminal portion -free of microtubule-binding domain -of the tau protein in cerebellar granule neurons (CGNs). We found that while the expression of the tau (1-230) fragment, as well as of full-length tau, inhibits the onset of apoptosis, the tau (1-44) fragment exerts a powerful toxic action on the same neurons. The antiapoptotic action of tau (1-230) is exerted at the level of Akt-mediated activation of the caspase cascade. On the other hand, the toxic action of the (1-44) fragment is not prevented by inhibitors of CGN apoptosis, but is fully inhibited by NMDA receptor antagonists. These findings point to a novel, physiological role of the N-terminal domain of tau, but also underlay that its possible proteolytic truncation mediated by apoptotic proteases may generate a highly toxic fragment that could contribute to neuronal death.

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“…Because of these differences, it is argued that human Tau, but not murine Tau, can exert neurotoxic effects. However, this hypothesis is contrasted by data showing that endogenous mouse Tau is required for Aβ-induced postsynaptic dysfunction and behavioral defects, [17][18][19][20][21][22][23][24] which suggest that murine Tau can carry out pathogenic functions that resemble that of human Tau AD.…”

Section: Introductionmentioning

confidence: 95%

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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Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

Cited by 192 publications

References 62 publications

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

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

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

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

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