The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology
Open accessAbstract
Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid β (Aβ) 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 (ΔTau) by executioner caspases. Following caspase-cleavage, ΔTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. ΔTau can be phosphorylated by glycogen synthase kinase-3β and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, ΔTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, ΔTau colocalizes with Aβ1–42 and is induced by Aβ1–42 in vitro. Collectively, our data imply that Aβ 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.
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“This is consistent with the observation that C-terminal truncated forms of Tau show increased polymerization capacity in vitro and are associated with NFTs formation in the brain of AD patients (Gamblin et al., 2003; Rissman et al., 2004).”
From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Rissman et al., 2004
In the citing paper
“Δtau levels were below the detectable level in our 7-month-old, untreated 3xTg-AD mice”
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 Rissman et al., 2004
In the citing paper
“Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010).”
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 Rissman et al., 2004
In the citing paper
“only caspase-2, 3 and 6 cleaved tau products have been linked to AD [190–193].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Although tau can be cleaved by caspase-1, 2, 3, 6 and 7 in vitro”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Tau-421 colocalizes with NFTs in human AD brain, and correlates with NFT formation and cognitive impairment in aged mice [191, 192, 194].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
In the citing paper
“Elevated levels of caspase-3 and tau-421 have been observed in AD, as well as PSP [130, 191, 192].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [192]
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Citations
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Amyloid Precursor Protein Processing and Alzheimer's Disease
O'Brien, R. J., & Wong, P. C. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113613 · Cited by 2,061
Fricker, M., Tolkovsky, A. M., Borutaitė, V., Coleman, M. P., & Brown, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00011.2017 · Cited by 1,148
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003
Tau pathology in Alzheimer disease and other tauopathies
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Metadata
- Authors
- Rissman, R. A., Poon, W. W., Blurton-Jones, M., Oddo, S., Torp, R., Vitek, M. P., LaFerla, F. M., Rohn, T. T., & Cotman, C. W.
- Affiliations
- University of California, Irvine (US)
- Duke Medical Center (US)
- Boise State University (US)
- Corresponding author
- Cotman, Carl W.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-07-01
- Volume
- 114
- Issue
- 1
- Pages
- 121-130
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC437967
- OpenAlex
- W1989856924
- Cited by
- 543
- References
- 82
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 20 · 2023: 20 · 2022: 20 · 2021: 23 · 2020: 32 · 2019: 28 · 2018: 33 · 2017: 24 · 2016: 30 · 2015: 26 · 2014: 19 · 2013: 27 · 2012: 30
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ScholarWorks (Boise State University) (submittedVersion)
- Funders
- National Institutes of Health (1r03ag019386-01, AG016573, AG000096, AG000538)
- National Institute on Aging (P01AG000538, AG19386, AG19780, AG-000538, AG17968, AG000096, R01AG017968, P50AG016573, F32AG023433, AG023433, R01AG019780, T32AG000096)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- tau cleavage, caspase activation, neurofibrillary tangles, Alzheimer's disease, amyloid-beta, glycogen synthase kinase-3β, tau phosphorylation, PHF1, cognitive decline, mild cognitive impairment, traumatic brain injury, triple transgenic mouse model
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Proteins, Mice, Transgenic, Phosphorylation, Reference Values, Neurofibrillary Tangles, tau Proteins, Pyramidal Cells, Mice, Knockout, Caspases, Mice, Presenilin-1
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