Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase

A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein ( PICALM/CALM ) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics. CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al. show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.