GSE127892
The major risk factors for Alzheimer's disease: Age, Sex and Genes, modulate the microglia response to Aß plaques (KW)
Microglia are involved in Alzheimer's disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of ß-amyloid (Aß) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aß deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aß exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors. Overall design: RNA-Seq of cortical and hippocampal microglia in female and male C57Bl/6 wild type mice and in AppNL-G-F mice M3, M6, M12, M21 (32 experimental conditions, 2 mice per condition - data pooled).