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

Published

Journal Article

Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid beta (Abeta) 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 (DeltaTau) by executioner caspases. Following caspase-cleavage, DeltaTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. DeltaTau can be phosphorylated by glycogen synthase kinase-3beta and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, DeltaTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, DeltaTau colocalizes with Abeta(1-42) and is induced by Abeta(1-42) in vitro. Collectively, our data imply that Abeta 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.

Full Text

Duke Authors

Cited Authors

  • Rissman, RA; Poon, WW; Blurton-Jones, M; Oddo, S; Torp, R; Vitek, MP; LaFerla, FM; Rohn, TT; Cotman, CW

Published Date

  • July 1, 2004

Published In

Volume / Issue

  • 114 / 1

Start / End Page

  • 121 - 130

PubMed ID

  • 15232619

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI20640

Language

  • eng

Conference Location

  • United States