The role of caspase cleavage of tau in Alzheimer disease neuropathology.
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques and neurofibrillary tangles within selective brain regions. In addition, cell death pathways become active leading to neurodegeneration. Caspase activation, a key step in the programmed cell death pathway known as apoptosis, occurs in AD and leads to the proteolytic cleavage of several neuronal proteins. Previously, it was hypothesized that the development of the classical hallmarks of AD, amyloid plaques and neurofibrillary tangles, occur independently and do not involve the activation of caspases. However, recent studies suggest that plaques, tangles, and caspase activation share a common pathway. Beta-amyloid, the main component of amyloid plaques, activates caspases. Activated caspases can in turn cleave tau, the main component of neurofibrillary tangles. Caspase-cleaved tau (deltatau) may initiate or accelerate the development of tangle pathology. Tau, when cleaved by caspases at Asp421, "seeds" filamentous aggregates in vitro. Caspase-cleaved tau also adopts the MC1 conformation, one of the earliest pathologic events in tangle formation. Importantly, deltatau occurs early in the development of tangle pathology within AD brains and in a transgenic mouse model of AD. This review summarizes recent evidence suggesting that caspase cleavage of tau plays an important role in the development of neurofibrillary tangle pathology. In addition, a model is presented whereby caspase cleavage of tau provides a mechanistic link between the development of amyloid and tangle pathologies.
Cotman
Carl W
CW
Institute for Brain Aging and Dementia, University of California, Irvine, 92697, USA. cwcotman@uci.edu
Poon
Wayne W
WW
Rissman
Robert A
RA
Blurton-Jones
Mathew
M
D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008959:Models, Neurological; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D020169:Caspases