title: Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.
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.
authors.affiliation: Institute for Brain Aging and Dementia, University of California, Irvine 92697, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rissman
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Reidun
authors.initials: R
authors.lastname: Torp
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: Troy T
authors.initials: TT
authors.lastname: Rohn
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010766:Phosphorylation; D053764:Presenilin-1; D017966:Pyramidal Cells / Q000473:pathology; D012016:Reference Values; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D020169:Caspases