Original Research ARTICLE
Effects of APOE Genotype on Brain Proteomic Network and Cell Type Changes in Alzheimer’s Disease
- 1Department of Neurology, Emory University, United States
- 2Department of Neurology, Emory University, United States
- 3Department of Biochemistry, Emory University School of Medicine, United States
- 4Center for Neurodegenerative Diseases, Emory University School of Medicine, United States
- 5Department of Neurology, Second Xiangya Hospital, Central South University, China
- 6Emory University, United States
- 7Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, United States
- 8Atlanta VA Health Care System, United States
- 9Department of Human Genetics, Emory University School of Medicine, United States
Polymorphic alleles in the apolipoprotein E (APOE) gene are the main genetic determinants of late-onset Alzheimer’s disease (AD) risk. Individuals carrying the APOE E4 allele are at increased risk to develop AD compared to those carrying the more common E3 allele, whereas those carrying the E2 allele are at decreased risk for developing AD. How ApoE isoforms influence risk for AD remains unclear. To help fill this gap in knowledge, we performed a comparative unbiased mass spectrometry-based proteomic analysis of post-mortem brain cortical tissues from pathologically-defined AD or control cases of different APOE genotypes. Control cases (n=10) were homozygous for the common E3 allele, whereas AD cases (n=24) were equally distributed among E2/3, E3/3, and E4/4 genotypes. We used differential protein expression and co-expression analytical approaches to assess how changes in the brain proteome are related to APOE genotype. We observed similar levels of amyloid-β, but reduced levels of neurofibrillary tau, in E2/3 brains compared to E3/3 and E4/4 AD brains. Weighted co-expression network analysis revealed 33 modules of co-expressed proteins, 12 of which were significantly different by APOE genotype in AD. The modules that were significantly different by APOE genotype were associated with synaptic transmission and inflammation, among other biological processes. Deconvolution and analysis of brain cell type changes revealed that the E2 allele suppressed homeostatic and disease-associated cell type changes in astrocytes, microglia, oligodendroglia, and endothelia. The E2 allele-specific effect on brain cell type changes was validated in a separate cohort of 130 brains. Our systems-level proteomic analyses of AD brain reveal alterations in the brain proteome and brain cell types associated with allelic variants in APOE, and suggest further areas for investigation into the upstream mechanisms that drive ApoE-associated risk for AD.
Keywords: Alzheimer's disease, Proteomics, Apolipoprotein E, Inflammation, deconvolution
Received: 10 Aug 2018;
Accepted: 23 Nov 2018.
Edited by:Nikhat Ahmed, Barrett Hodgson University, Pakistan
Reviewed by:VICTORIA CAMPOS-PEÑA, Instituto Nacional de Neurología y Neurocirugía (INNN), Mexico
Maciej M. Lalowski, University of Helsinki, Finland
Copyright: © 2018 Dai, Johnson, Dammer, Duong, Gearing, Lah, Levey, Wingo and Seyfried. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dr. Erik C. Johnson, Emory University, Atlanta, United States, firstname.lastname@example.org
Dr. Nicholas T. Seyfried, Department of Neurology, Emory University, Atlanta, 30322, Georgia, United States, email@example.com