Pathway-based analysis of genome-wide siRNA screens reveals the regulatory landscape of APP processing

• Published in: PloS one Vol. 10; no. 2; p. e0115369
• Main Authors: Camargo, Luiz Miguel, Zhang, Xiaohua Douglas, Loerch, Patrick, Caceres, Ramon Miguel, Marine, Shane D, Uva, Paolo, Ferrer, Marc, de Rinaldis, Emanuele, Stone, David J, Majercak, John, Ray, William J, Yi-An, Chen, Shearman, Mark S, Mizuguchi, Kenji
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.02.2015; Public Library of Science (PLoS)
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloidogenesis; Bias; Bioinformatics; Biological activity; Biological products; Biology; Brain; Cell Survival; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; Enzymes; Gene expression; Genetic screening; Genetic Techniques; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Humans; Identification; Insulin; Kinases; Laboratories; Metabolic Networks and Pathways; Neurodegenerative diseases; Ontology; Pancreas; Pathogenesis; Peptide Fragments - metabolism; Peptides; Protein Processing, Post-Translational; Proteins; Proteolysis; Regulators; Regulatory mechanisms (biology); RNA, Small Interfering - analysis; Serum Amyloid A Protein - metabolism; siRNA; Synaptic transmission; Vaccines; β-Amyloid; Italy; United Kingdom > UK; United States > US; Japan; Wales
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115369

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.