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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.

Original publication

DOI

10.1074/jbc.M111.288258

Type

Journal article

Journal

J Biol Chem

Publication Date

06/01/2012

Volume

287

Pages

1100 - 1111

Keywords

ATP-Binding Cassette Transporters, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Animals, Down-Regulation, Drosophila Proteins, Drosophila melanogaster, HEK293 Cells, Humans, Membrane Glycoproteins, Mice, Nerve Tissue Proteins, Rats