First Author | Udayar V | Year | 2013 |
Journal | Cell Rep | Volume | 5 |
Issue | 6 | Pages | 1536-51 |
PubMed ID | 24373285 | Mgi Jnum | J:204128 |
Mgi Id | MGI:5529702 | Doi | 10.1016/j.celrep.2013.12.005 |
Citation | Udayar V, et al. (2013) A Paired RNAi and RabGAP Overexpression Screen Identifies Rab11 as a Regulator of beta-Amyloid Production. Cell Rep 5(6):1536-51 |
abstractText | Alzheimer's disease (AD) is characterized by cerebral deposition of beta-amyloid (Abeta) peptides, which are generated from amyloid precursor protein (APP) by beta- and gamma-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Abeta 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 Abeta production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled beta-secretase endosomal recycling to the plasma membrane and thus affected Abeta 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 Abeta levels and show how systems biology approaches can unravel the molecular complexity underlying AD. |