【文章名】Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-beta Production by Altering Nicastrin Maturation and Intracellular Localization
Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-beta Production by Altering Nicastrin Maturation and Intracellular Localization
[摘要]：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.
