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

作者：Michaki Vasiliki; Guix Francesc X; Vennekens Krist' l; Munck Sebastian; Dingwall Colin; Davis John B; Townsend Danyelle M; Tew Kenneth D; Feiguin Fabian; De Strooper Bart; Dotti Carlos G^*; Wahle Tina

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(2): 1100-1111.

DOI：10.1074/jbc.M111.288258

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.

• 出版日期2012-1-6