Identifying complement‐related proteins expression pattern of different APOE genotypes in patients with Alzheimer’s disease

Abstract

AbstractBackgroundApolipoprotein E (APOE) gene is one of the strongest risk factors found for late‐onset Alzheimer’s disease (AD). Complement pathways are implicated in AD. The objective of this project was to examine the difference of complement related proteins expression and networks between AD and healthy control of the same genotype.MethodTwo publicly available label free quantification (LFQ) mass spectrometry brain proteomics datasets were used. The Emory cohort consisted of 4,774 protein groups for 10 controls (E3/E3) and 24 autopsy‐confirmed AD (8 of each genotype of E2/E3, E3/E3, and E3/E4); the Banner cohort of 5,711 protein groups for 77 controls (18 E2/E3 and 59 E3/E3) and 44 autopsy‐confirmed AD (6 E2/E3, 30 E3/E3, and 8 E4/E4). Each proteomics dataset was screened by a list of complement‐related proteins identified in Uniprot database using “Complement protein” as the keyword. Differential analyses were conducted using R package DEP for AD compared to control (non‐AD) group with the same genotype. Correlation analysis using R package WGCNA (Weighted correlation network analysis) was performed to cluster similar proteins into modules. The identified modules are then correlated with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden. Finally, protein functional enrichment analysis was conducted using DAVID (DAVID Bioinformatics Resources 6.8).ResultComplement proteins are highly expressed in AD (n = 36) than controls (n = 64) in genotype of E3/E3 and in AD (n = 17) than controls (n = 49) in genotype of E3/E4 in the Banner cohort (p‐value < 0.05, log‐fold‐change > log[1.5]). For both cohorts, one module is identified to have a positive correlation with APOE genotypes, tau tangle burden and neurotic amyloid plaque burden (p‐value < 0.05, correlation coefficient > 0.35). Proteins in those modules were involved in classical complement pathway and immunity innate, mitochondrial ribosomal proteins, and proteins related to Alpha‐2‐macroglobulin and extracellular exosome.ConclusionOur results suggest significant differential expressions of complement‐related proteins in AD, independent of APOE genotypes. This may provide potential biomarkers and therapeutic target related to complement pathways for AD.