Calpain-mediated tau fragmentation is altered in Alzheimer’s disease progression
Open accessAbstract
The aggregation of intracellular tau protein is a major hallmark of Alzheimer’s disease (AD). The extent and the stereotypical spread of tau pathology in the AD brain are correlated with cognitive decline during disease progression. Here we present an in-depth analysis of endogenous tau fragmentation in a well-characterized cohort of AD and age-matched control subjects. Using protein mass spectrometry and Edman degradation to interrogate endogenous tau fragments in the human brain, we identified two novel proteolytic sites, G323 and G326, as major tau cleavage events in both normal and AD cortex. These sites are located within the sequence recently identified as the structural core of tau protofilaments, suggesting an inhibitory mechanism of fibril formation. In contrast, a different set of novel cleavages showed a distinct increase in late stage AD. These disease-associated sites are located outside of the protofilament core sequence. We demonstrate that calpain 1 specifically cleaves at both the normal and diseased sites in vitro, and the site selection is conformation-dependent. Monomeric tau is predominantly cleaved at G323/G326 (normal sites), whereas oligomerization increases cleavages at the late-AD-associated sites. The fragmentation patterns specific to disease and healthy states suggest novel regulatory mechanisms of tau aggregation in the human brain.
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Calpain-2 cleaves tau at Arg230.
“while calpain-2 cleaves tau at Arg230 [202–206].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [206]
Calpain-1 cleaves tau at Lys44, Arg230, Arg242, Gly323, and Gly326.
“Calpain-1 cleaves tau at Lys44, Arg230, Arg242, Gly323, and Gly326”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [206]
Aβ triggers activation of caspase-3 and calpain-1, which can cleave Tau at the C-terminus generating small fragments able to induce neurite degeneration and neuronal death.
“Moreover, Aβ triggers the activation of caspase-3 and calpain-1, which can cleave Tau at the C-terminus generating small fragments able to induce neurite degeneration and neuronal death (Gamblin et al., 2003; Bloom, 2014; Chen et al., 2018).”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Chen et al., 2018
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- Authors
- Chen, H.-H., Liu, P., Auger, P., Lee, S.-H., Adolfsson, O., Rey-Bellet, L., Lafrance-Vanasse, J., Friedman, B. A., Pihlgren, M., Muhs, A., Pfeifer, A., Ernst, J., Ayalon, G., Wildsmith, K. R., Beach, T. G., & van der Brug, M. P.
- Affiliations
- Genentech (US)
- AC Immune (Switzerland) (CH)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Chen, Hsu-Hsin
- ORCID
- Venue
- Scientific Reports
- Published
- 2018-11-13
- Volume
- 8
- Issue
- 1
- Pages
- 16725-16725
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6233188
- OpenAlex
- W2899521216
- Cited by
- 51
- References
- 62
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 8 · 2019: 3
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (U24 NS072026, 05-901, 211002, P30 AG19610)
- Sun Health Foundation (P30 AG19610, 211002, 05-901, U24 NS072026)
- Arizona Department of Health Services (P30 AG19610, U24 NS072026, 05-901, 211002, Contract 211002)
- Arizona Biomedical Research Commission (P30 AG19610, 05–901, Contracts 4001, 0011, 05‐901 and 1001, U24 NS072026, 4001, 0011, 05-901, and 1001, 211002)
- National Institute on Aging (211002, P30-AG-19610, AG-19610, P30AG019610, 05-901)
- National Institute of Neurological Disorders and Stroke (NS072026, 211002, U24NS072026, 05-901, U24 NS072026 National Brain, P30 AG19610)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, calpain-1, Alzheimer's disease, tau aggregation, proteolytic cleavage, tau oligomerization, disease progression, cerebral cortex
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Brain, Calpain, Female, Humans, Male, tau Proteins, Disease Progression, Proteolysis
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