American Society for Biochemistry and Molecular Biology
Journal of Biological Chemistry vol:287 issue:2 pages:1100-1111
Clinical, pharmacological, biochemical and genetic evidences support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimers 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-β (Aβ) generation. In vitro studies revealed altered γ-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 γ-secretase processing of APP, and thus the generation of Aβ, without affecting Notch cleavage.