title: 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.
authors.affiliation: Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
authors.forename: Kunie
authors.initials: K
authors.lastname: Ando
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Brion
authors.forename: Virginie
authors.initials: V
authors.lastname: Stygelbout
authors.forename: Valérie
authors.initials: V
authors.lastname: Suain
authors.forename: Michèle
authors.initials: M
authors.lastname: Authelet
authors.forename: Robert
authors.initials: R
authors.lastname: Dedecker
authors.forename: Anaïs
authors.initials: A
authors.lastname: Chanut
authors.forename: Pascale
authors.initials: P
authors.lastname: Lacor
authors.forename: Jérémie
authors.initials: J
authors.lastname: Lavaur
authors.forename: Véronique
authors.initials: V
authors.lastname: Sazdovitch
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D004314:Down Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D017628:Microglia / Q000502:physiology; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D016875:tau Proteins