title: Calmodulin regulates the non-amyloidogenic metabolism of amyloid precursor protein in platelets.
abstract: A balance between the proteolytic processing of amyloid precursor protein APP through the amyloidogenic and the non-amyloidogenic pathways controls the production and release of amyloid β-protein, whose accumulation in the brain is associated to the onset of Alzheimer Disease. APP is also expressed on circulating platelets. The regulation of APP processing in these cells is poorly understood. In this work we show that platelets store considerable amounts of APP fragments, including sAPPα, that can be released upon stimulation of platelets. Moreover, platelet stimulation also promotes the proteolysis of intact APP expressed on the cell surface. This process is supported by an ADAM metalloproteinase, and causes the release of sAPPα. Processing of intact platelet APP is promoted also by treatment with calmodulin antagonist W7. W7-induced APP proteolysis occurs through the non-amyloidogenic pathway, is mediated by a metalloproteinase, and causes the release of sAPPα. Co-immunoprecipitation and pull-down experiments revealed a physical association between calmodulin and APP. These results document a novel role of calmodulin in the regulation of non-amyloidogenic processing of APP.
authors.affiliation: Department of Biochemistry, University of Pavia, via Bassi 21, 27100 Pavia, Italy. ilaria.canobbio@unipv.it
authors.forename: I
authors.initials: I
authors.lastname: Canobbio
authors.forename: S
authors.initials: S
authors.lastname: Catricalà
authors.forename: C
authors.initials: C
authors.lastname: Balduini
authors.forename: M
authors.initials: M
authors.lastname: Torti
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D015539:Platelet Activation; D011485:Protein Binding; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D002147:Calmodulin; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C017967:W 7