Activation of Microglial Genes and Crosstalk with Micro-environment in Modulating Immunological Pathology in Alzheimer's Disease

Abstract

Recent studies have revealed that immune responses and related pathways are actively involved into the progression of Alzheimer's disease (AD) / AD-like pathology in both patients and disease models. Single-cell studies further discovered the accumulation of disease associated microglia (DAM) along with the progression of AD pathology and the pro-inflammatory activity was regulated by the Trem2-dependent pathways. Given the significance of microglia population in mediating the clearance of plaques, it is important to understand the mechanism of microglia activation and their response changes to the plaque accumulation in AD-affected brains. By observing the gene expression level across brain regions in 5xFAD mice, we showed that hippocampus was most affected during AD-like pathology progression and most up-regulated genes were pro-inflammatory. Then, by looking at the microglia gene expression data, we revealed the distinguished activation of disease-associated immune responses at the late stage in 5xFAD mice and the discrepancy between 5xFAD and wild type mice was increased with aging. In addition, we discussed the importance of Trem2 in microglia at the late stage of 5xFAD and showed that Trem2 knock-out not only decreased microglia immune responses but also changed the micro-environment that microglia resided in. Based on this, we continued argued that the interaction between microglia and other cell types, including neurons, astrocytes and oligodendrocytes, had significant impacts on the microglia-mediated plaque clearance in AD/AD-like pathology affected brain tissues.