Michaki, V., Guix, F.X., Vennekens, K., Munck, S., Dingwall, C., Davis, J.B., Townsend, D.M., Tew, K.D., Feiguin, F., De Strooper, B., Dotti, C.G., Wahle, T. (2012). Down-regulation of the ATP-binding Cassette Transporter 2 (Abca2) Reduces Amyloid-β Production by Altering Nicastrin Maturation and Intracellular Localization.  J. Biol. Chem. 287(2): 1100--1111.

FBrf0217159

Research paper

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-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 Aβ generation, without affecting Notch cleavage.

PMC3256850 (PMC) (EuropePMC)