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

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

Research output: Contribution to journalArticle

369 Citations (Scopus)

Abstract

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 MCI. 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 Aβ1-42 and is induced by Aβ1-42 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.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalJournal of Clinical Investigation
Volume114
Issue number1
DOIs
StatePublished - Jul 2004
Externally publishedYes

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Neurofibrillary Tangles
Caspases
Alzheimer Disease
Pathology
Glycogen Synthase Kinase 3
Cytoskeletal Proteins
Amyloid Plaques
Transgenic Mice
Antibodies
Brain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rissman, R. A., Poon, W. W., Blurton-Jones, M., Oddo, S. ., Torp, R., Vitek, M. P., ... Cotman, C. W. (2004). Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. Journal of Clinical Investigation, 114(1), 121-130. https://doi.org/10.1172/JCI200420640

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.

In: Journal of Clinical Investigation, Vol. 114, No. 1, 07.2004, p. 121-130.

Research output: Contribution to journalArticle

Rissman, RA, Poon, WW, Blurton-Jones, M, Oddo, S, Torp, R, Vitek, MP, LaFerla, FM, Rohn, TT & Cotman, CW 2004, 'Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology', Journal of Clinical Investigation, vol. 114, no. 1, pp. 121-130. https://doi.org/10.1172/JCI200420640
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. / Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 1. pp. 121-130.
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