The Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology

Cotman, Carl W.; Poon, Wayne W.; Rissman, Robert A.; Blurton-Jones, Mathew

doi:10.1093/jnen/64.2.104

Cited by 199Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology

Cotman, Carl W., Poon, Wayne W., Rissman, Robert A., Blurton-Jones, Mathew·2005·Journal of Neuropathology & Experimental Neurology

DOI 10.1093/jnen/64.2.104

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Abstract

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.

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Early cleavage of tau by caspases may contribute to cognitive decline.
“may contribute to cognitive decline”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Cotman et al., 2005
Early cleavage of tau by caspases initiates tau aggregation and phosphorylation.
“the early cleavage of tau by these caspases initiates tau aggregation and phosphorylation”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Cotman et al., 2005
During characterization of PHFs isolated from the brains of individuals with AD, tau had undergone carboxy-terminal truncation by caspase-3.
“During the characterization of PHFs isolated from the brains of individuals with AD, it was discovered that tau had undergone carboxy-terminal truncation by caspase-336,37.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [36]
In AD, Aβ promotes caspase activation, providing a link between the two main pathologies.
“In the case of AD, Aβ promotes caspase activation, thereby providing a link between the two main pathologies36.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [36]

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Authors: Cotman, C. W., Poon, W. W., Rissman, R. A., & Blurton-Jones, M.
Affiliations: University of California, Irvine (US)
Corresponding author: Cotman, Carl W.
ORCID: Cotman, Carl W.
Poon, Wayne W.
Rissman, Robert A.
Blurton-Jones, Mathew
Venue: Journal of Neuropathology & Experimental Neurology
Publisher: Oxford University Press (OUP)
Published: 2005-02
Volume: 64
Issue: 2
Pages: 104-112
ISSN: 0022-3069 (ISSN-L)
1554-6578
DOI: 10.1093/jnen/64.2.104
OpenAlex: W99707707
Cited by: 199
References: 85
Citations by year: 2026: 1 · 2025: 7 · 2024: 10 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 3 · 2014: 2 · 2013: 14 · 2012: 12
FWCI: 2.42
Type: journal article
Language: en
Open access: closed
Locations: Journal of Neuropathology & Experimental Neurology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (P01AG000538, P50AG016573, F32-AG0234333)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, neurofibrillary tangles, amyloid plaques, amyloid-beta, apoptosis, neurodegeneration, tau conformation, tau aggregation, transgenic mouse model
MeSH terms: Alzheimer Disease, Animals, Brain, Enzyme Activation, Humans, Models, Neurological, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Caspases

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The Role of Caspase Cleavage of Tau in Alzheimer Disease Neuropathology

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