Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-beta Production by Altering Nicastrin Maturation and Intracellular Localization

Clinical, pharmacological, biochemical, and genetic evidence support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimer disease (AD). The ATP-binding cassette transporter-2 (Abca2), which plays a role in intracellular sterol trafficking, has been genetically linked to AD. It is unclear how these two processes are related. Here we demonstrate that down-regulation of Abca2 in mammalian cells leads to decreased amyloid-beta (A beta) generation. In vitro studies revealed altered gamma-secretase complex formation in Abca2 knock-out cells due to the altered levels, post-translational modification, and subcellular localization of Nicastrin. Reduced Abca2 levels in mammalian cells in vitro, in Drosophila melanogaster and in mice resulted in altered gamma-secretase processing of APP, and thus A beta generation, without affecting Notch cleavage.