Increased monocyte activity identified in Alzheimer’s disease by in depth single‐cell genomic and proteomic analysis

Abstract

AbstractBackgroundAlzheimer’s disease (AD) patients show sustained levels of inflammation in the brain and the peripheral immune system. It is not known how various peripheral blood mononuclear cells (PBMCs) differ in AD patients and whether those differences can act as biomarkers of AD. Here we performed a multi‐omic profiling of PBMCs from AD patients and compared the composition of their cell type and cell state as well as their gene and protein expression to normal controls.MethodSingle‐cell proteogenomics analysis was performed on PBMCs from 20 AD patients and 15 controls using Singleron Biotechnologies’ ESCAPE platform. Seven of the AD and four control samples were additionally analyzed for bulk protein expression using Sciomics’ scioDiscover platform.ResultBulk proteomics identified 100 proteins with a significant differential abundance between AD patients and controls. Data point to a higher platelet activation and degranulation, as well as changes in the EGFR / MAPK3 and VEGF signaling in AD. As an individual marker CD163 was identified at a higher abundance in AD PBMCs pointing to an increase in monocyte / macrophage activity.From the single‐cell analysis we found that AD patients had significantly more CD14+ monocytes. We further found that the CD14+ monocytes could be split into seven clusters based on their gene expression with only two clusters having a significantly higher number of cells in AD patients. One of the overrepresented clusters showed high expression of Alarmin genes, suggesting an increased inflammatory environment, while the other cluster showed a higher level of HLA expression suggesting a state primed for activation.ConclusionWe found significant changes in both gene and protein expression in PBCMs from AD patients that indicate an increased inflammatory state . While there was a good overlap of findings between gene and protein expression, some of the changes are only seen at the protein level, while others are only observed at the level of gene expression. The combination of the two measurement techniques provides us with additional insights into inflammatory nature of the peripheral immune system in AD patients and provide hints at the mechanisms different cells use to generate those inflammatory signals.