A paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of ?-amyloid production.
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ABSTRACT: Alzheimer's disease (AD) is characterized by cerebral deposition of ?-amyloid (A?) peptides, which are generated from amyloid precursor protein (APP) by ?- and ?-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls A? levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating A? production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled ?-secretase endosomal recycling to the plasma membrane and thus affected A? production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate A? levels and show how systems biology approaches can unravel the molecular complexity underlying AD.
SUBMITTER: Udayar V
PROVIDER: S-EPMC4004174 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
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