Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains
Abstract
PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.
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PICALM is known to be expressed in brain MGs.
“While PICALM is known to be expressed in brain MGs51, and its role in lipid/cholesterol metabolism has been reported in Drosophila glia and HEK293 cells13,36, our work demonstrates a human-MG-specific role for PICALM in regulating LD accumulation and phagocytosis, which potentially contribute to LOAD pathophysiology.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [51]
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“While PICALM is known to be expressed in brain MGs 51 , and its role in lipid/cholesterol metabolism has been reported in Drosophila glia and HEK293 cells 13,36 , our work demonstrates a human-MG-specific role for PICALM in regulating LD accumulation and phagocytosis, which potentially contribute…”
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- Authors
- Ando, K., Brion, J.-P., Stygelbout, V., Suain, V., Authelet, M., Dedecker, R., Chanut, A., Lacor, P., Lavaur, J., Sazdovitch, V., Rogaeva, E., Potier, M.-C., & Duyckaerts, C.
- Affiliations
- Université Libre de Bruxelles (BE)
- Assistance Publique – Hôpitaux de Paris (FR)
- Northwestern University (US)
- Centre National de la Recherche Scientifique (FR)
- University of Toronto (CA)
- Corresponding author
- Duyckaerts, Charles
- Venue
- Acta Neuropathologica
- Published
- 2013-04-16
- Volume
- 125
- Issue
- 6
- Pages
- 861-878
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2052818071
- Cited by
- 136
- References
- 11
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 7 · 2023: 9 · 2022: 9 · 2021: 19 · 2020: 11 · 2019: 10 · 2018: 10 · 2017: 11 · 2016: 14 · 2015: 7 · 2014: 11 · 2013: 1
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Agence Nationale de la Recherche
- 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
- PICALM, clathrin adaptor proteins, Alzheimer's disease, neurofibrillary tangles, proteolytic cleavage, calpain, caspases, tau hyperphosphorylation, PHF-tau, microglia, clathrin-mediated endocytosis, familial Alzheimer's disease, Down syndrome, genetic risk factors
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Down Syndrome, Female, Humans, Male, Middle Aged, Case-Control Studies, Neurofibrillary Tangles, tau Proteins, Microglia, Monomeric Clathrin Assembly Proteins
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