The Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology

• Published in: Journal of neuropathology and experimental neurology Vol. 64; no. 2; pp. 104 - 112
• Main Authors: Cotman, Carl W, Poon, Wayne W, Rissman, Robert A, Blurton-Jones, Mathew
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.02.2005; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Animals; Biological and medical sciences; Brain - enzymology; Brain - pathology; Caspases - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzyme Activation; Humans; Medical sciences; Models, Neurological; Nervous system involvement in other diseases. Miscellaneous; Neurofibrillary Tangles - chemistry; Neurofibrillary Tangles - pathology; Neurology; tau Proteins - chemistry; tau Proteins - metabolism; Nervous system diseases; Enzyme; Alzheimer disease; Cysteine endopeptidases; Caspase; Tau; Activation; Cerebral disorder; Peptidases; Caspase activation; Tau protein; Central nervous system disease; Hydrolases; Cleavage; Degenerative disease; Amyloid
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/64.2.104

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. β-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 (Δtau) may initiate or accelerate the development of tangle pathology. Tau, when cleaved by caspases at Asp, "seeds" filamentous aggregates in vitro. Caspase-cleaved tau also adopts the MC1 conformation, one of the earliest pathologic events in tangle formation. Importantly, Δtau 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.