{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T18:49:28Z","timestamp":1769626168950,"version":"3.49.0"},"reference-count":96,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Belgian FRS-FNRS"},{"DOI":"10.13039\/501100002661","name":"Belgian Fonds de la Recherche Scientifique M\u00e9dicale","doi-asserted-by":"publisher","award":["T.0023.15"],"award-info":[{"award-number":["T.0023.15"]}],"id":[{"id":"10.13039\/501100002661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fund Aline (King Baudouin Foundation)"},{"name":"Belgian Fondation Recherche Alzheimer\/Stichting Alzheimer Onderzoek"},{"name":"ULB G\u00e9nicot Fund"},{"DOI":"10.13039\/501100022601","name":"Fondation M\u00e9dicale Reine Elisabeth","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022601","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a clathrin adaptor essential for clathrin-mediated endocytosis. Genome-wide association studies (GWAS) have consistently identified PICALM as one of the most significant genetic susceptibility loci for late-onset sporadic Alzheimer\u2019s disease (AD). However, the functional impact of the most validated AD-associated variant, rs3851179, remains unclear. Here, we examined PICALM mRNA and protein expression in post-mortem AD brains with reference to rs3851179 genotype. We found that PICALM mRNA levels were significantly increased in AD brains compared with controls, and that the protective rs3851179T allele was associated with reduced PICALM mRNA levels relative to the non-protective rs3851179C allele. In contrast, PICALM levels were significantly reduced in AD brain lysates compared with controls. PICALM expression did not significantly differ between carriers of the protective and non-protective alleles. Analysis of the mRNA-to-protein ratio revealed a significant dissociation between transcript and protein levels, suggesting relatively reduced protein expression efficiency in cases carrying the non-protective CC genotype. To assess whether reduced PICALM levels influence tau pathology, we used Picalm heterozygous knockout (Picalm+\/\u2212) mice, which express approximately 50% of the wild-type Picalm protein. Following stereotaxic injection of pathological tau extracted from AD brains, both wild-type and Picalm+\/\u2212 mice developed tau pathology; however, the extent of tau accumulation did not significantly differ between genotypes. Together, these findings indicate that although PICALM protein level is reduced in AD, this reduction does not appear to affect tau propagation in this model. Therefore, the AD susceptibility associated with PICALM variant likely arises from mechanisms other than tau spread, possibly involving other aspects of autophagy, endocytic or vascular function.<\/jats:p>","DOI":"10.3390\/cells15030235","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T12:41:16Z","timestamp":1769431276000},"page":"235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PICALM Genetic Variant Alters mRNA Expression Without Affecting Protein Levels or Tau Spreading in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-175X","authenticated-orcid":false,"given":"Kunie","family":"Ando","sequence":"first","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-0505","authenticated-orcid":false,"given":"Lidia","family":"Lopez-Gutierrez","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salwa","family":"Mansour","sequence":"additional","affiliation":[{"name":"Laboratory of Histology, Neuropathology and Neuroanatomy, Faculty of Medicine, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zehra","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Laboratory of Histology, Neuropathology and Neuroanatomy, Faculty of Medicine, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luce","family":"Dauphinot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, APHP, H\u00f4pital de La Piti\u00e9-Salp\u00eatri\u00e8re, INSERM, F-75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0481-9649","authenticated-orcid":false,"given":"Jan","family":"Verheijen","sequence":"additional","affiliation":[{"name":"Complex Genetics of Alzheimer\u2019s Disease Group, VIB Center for Molecular Neurology, VIB Antwerp, B-2610 Antwerp, Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp, B-2610 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ga\u00eblle","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, APHP, H\u00f4pital de La Piti\u00e9-Salp\u00eatri\u00e8re, INSERM, F-75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-6162","authenticated-orcid":false,"given":"Carolina","family":"Quintanilla-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Aydin","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilie","family":"Doeraene","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8132-491X","authenticated-orcid":false,"given":"Siranjeevi","family":"Nagaraj","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-8522","authenticated-orcid":false,"given":"Andreea-Claudia","family":"Kosa","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2216-1581","authenticated-orcid":false,"given":"Toshio","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women\u2019s University, Nara 630-8506, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0283-2332","authenticated-orcid":false,"given":"Kristel","family":"Sleegers","sequence":"additional","affiliation":[{"name":"Complex Genetics of Alzheimer\u2019s Disease Group, VIB Center for Molecular Neurology, VIB Antwerp, B-2610 Antwerp, Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp, B-2610 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-7150","authenticated-orcid":false,"given":"Marie-Claude","family":"Potier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, APHP, H\u00f4pital de La Piti\u00e9-Salp\u00eatri\u00e8re, INSERM, F-75013 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-775X","authenticated-orcid":false,"given":"Jean-Pierre","family":"Brion","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8661-5262","authenticated-orcid":false,"given":"Karelle","family":"Leroy","sequence":"additional","affiliation":[{"name":"Alzheimer and Other Tauopathies Research Group, ULB Center for Diabetes Research, Medical Faculty, ULB Neuroscience Institute, Universit\u00e9 Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77sr71","DOI":"10.1126\/scitranslmed.3002369","article-title":"Alzheimer\u2019s disease: The challenge of the second century","volume":"3","author":"Holtzman","year":"2011","journal-title":"Sci. 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