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PMID: 15232619 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 114 ·No. 1 ·2004-07-00 ·Pages 121-30

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

Abstract

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.

MeSH Terms
Alzheimer Disease/enzymology,pathology Animals Caspases/metabolism Humans Membrane Proteins/genetics Mice Mice, Knockout Mice, Transgenic Neurofibrillary Tangles/pathology Phosphorylation Presenilin-1 Pyramidal Cells/pathology Reference Values tau Proteins/deficiency,genetics,metabolism
Chemicals
Membrane Proteins PSEN1 protein, human Presenilin-1 tau Proteins Caspases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Rissman Robert A
Institute for Brain Aging and Dementia, University of California, Irvine 92697, USA.
Poon Wayne W
Blurton-Jones Mathew
Oddo Salvatore
Torp Reidun
Vitek Michael P
LaFerla Frank M
Rohn Troy T
Cotman Carl W
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI20640
Published
2004-07-00
Pages
121-30
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC437967
Subset
IM
Grants
NIA NIH HHS · AG19780 · United States
NIA NIH HHS · P01 AG000538 · United States
NIA NIH HHS · R01 AG019780 · United States
NIA NIH HHS · AG17968 · United States
NIA NIH HHS · F32 AG023433 · United States
NIA NIH HHS · AG19386 · United States
NIA NIH HHS · P50 AG016573 · United States
NIA NIH HHS · R01 AG017968 · United States
NIA NIH HHS · T32 AG000096 · United States
NIA NIH HHS · AG000096 · United States
NIA NIH HHS · AG023433 · United States
NIA NIH HHS · AG000538 · United States
Corrections
CommentIn
PMID: 15232608
External Links
PubMed source DOI: 10.1172/JCI20640 PMC Full Text View journal details
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