biostudies-literatureUdayar VIntramural NIH HHSNIA NIH HHSNIDA NIH HHSMedical Research CouncilAlzheimers Research UKWellcome Trust1536-51https://www.ebi.ac.uk/biostudies/studies/S-EPMC4004174biostudies-literatureUnknown5(6)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.Cell reportsA paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of ?-amyloid production.PMC4004174AG021495Z01 AG000950R21 DA036086ZO1 AG000950-10ARUK-TRFUS2012-3R01 AG019070R01 AG021495WT089698AG019070ZIA AG000950-10MC_G1000735089698Siegel GRajendran LHardy JPuthenveedu MALupton MKRies JGuerreiro RSassi CPowell JBras JSoohoo ALSingleton AGuerreiro RLUdayar VHernandez DMorgan KGibbs JRPonnusamy MAESGBuggia-Prevot VThinakaran GBali JSimons MSiegenthaler BBrown KRambabu NfalseA paired RNAi and RabGAP overexpression screen identifies Rab11 as a regulator of ?-amyloid production.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.2013-01-01T00:00:00Z2013 Dec2020-11-19T10:03:43Z2019-03-27T01:27:17ZS-EPMC40041742437328510.1016/j.celrep.2013.12.005