Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-β production by altering nicastrin maturation and intracellular localization

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.

2012-01-01

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Abstract

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, inDrosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.