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-beta peptide (A beta) 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 A beta species, A beta 42. Active form of gamma-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of gamma-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of A beta 42. Our study identifies CALM as an endogenous modulator of gamma-secretase activity by regulating its endocytosis and also as an excellent target for A beta 42-lowering AD therapeutics.