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

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.Fund for Scientific Research Flanders (FWO); Federal Office for Scientific Affairs (IUAP P6/43/); Stichting voor Alzheimer Onderzooek/Fondation pour la Recherche sur Maladie d’ Alzheimer (SAO/FRMA), the Flemish Government (Methusalem grant); Spanish Government Grants Ministerio de Ciencia e Innovación (Ingenio Consolider CSD2010-00064); Ministerio de Ciencia e Innovación (SAF2010-14906)Peer Reviewe