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Downregulation of the ATP-binding cassette transporter 2 (Abca2) reduces Amyloid-β production by altering Nicastrin maturation and intracellular localization

Tijdschriftbijdrage - Tijdschriftartikel

Clinical, pharmacological, biochemical and genetic evidences support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimers 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 the generation of Aβ, without affecting Notch cleavage.
Tijdschrift: Journal of Biological Chemistry
ISSN: 0021-9258
Issue: 2
Volume: 287
Pagina's: 1100 - 1111
Jaar van publicatie:2012
BOF-publication weight:1
CSS-citation score:1
Authors from:Higher Education