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

PLoS One. 2015 Feb 27;10(2):e0115369. doi: 10.1371/journal.pone.0115369. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Cell Survival
  • Diabetes Mellitus, Type 2 / metabolism
  • Genetic Techniques*
  • Genome-Wide Association Study
  • Humans
  • Metabolic Networks and Pathways*
  • Peptide Fragments / metabolism
  • Protein Processing, Post-Translational
  • Proteolysis
  • RNA, Small Interfering / analysis*
  • Serum Amyloid A Protein / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • RNA, Small Interfering
  • Serum Amyloid A Protein
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)

Grant support

Merck & Co funded the work presented in this manuscript. All authors, with the exception of Kenji Mizuguchi (KM) and Chen Yi-An (CYA), were employed by Merck & Co during the time the research was conducted. The funder, Merck & Co provided support in the form of salaries for authors LMC, XDZ, PL, MC, SDM, PU, MF, EDR, DJS, JM, WJR and MSS during the course of the study, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Novartis, CRS4 Bioinformatica, Merck Serono, Boehringer Ingelheim, and Takeda Pharmaceuticals provided support in the form of salaries for authors LMC, PU, MS, JM, and WJR, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the‘author contributions’ section.