Pathway-based analysis of genome-wide siRNA screens reveals the regulatory landscape of APP processing.
The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP.
Merck Research Laboratories, Merck & Co, Boston, United States of America.
Luiz Miguel
LM
Camargo
Merck Research Laboratories, Merck & Co, Beijing, China.
Xiaohua Douglas
XD
Zhang
Merck Research Laboratories, Merck & Co, Boston, United States of America.
Patrick
P
Loerch
Merck Research Laboratories, Merck & Co, Boston, United States of America.
Ramon Miguel
RM
Caceres
Merck Research Laboratories, Merck & Co, North Wales, United States of America.
Shane D
SD
Marine
Merck Research Laboratories, Instituto di Recerca di Biologia Molecolare, Pomezia, Italy.
Paolo
P
Uva
Merck Research Laboratories, Merck & Co, North Wales, United States of America.
Marc
M
Ferrer
Merck Research Laboratories, Instituto di Recerca di Biologia Molecolare, Pomezia, Italy.
Emanuele
E
de Rinaldis
Merck Research Laboratories, Merck & Co, West Point, United States of America.
David J
DJ
Stone
Merck Research Laboratories, Merck & Co, West Point, United States of America.
John
J
Majercak
Merck Research Laboratories, Merck & Co, West Point, United States of America.
William J
WJ
Ray
National Institute of Biomedical Innovation, Osaka, Japan.
Chen
C
Yi-An
Merck Research Laboratories, Merck & Co, Boston, United States of America.
Mark S
MS
Shearman
National Institute of Biomedical Innovation, Osaka, Japan.
Kenji
K
Mizuguchi
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005821:Genetic Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D053858:Metabolic Networks and Pathways; D010446:Peptide Fragments / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000032:analysis*; D000685:Serum Amyloid A Protein / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D000685:Serum Amyloid A Protein; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)