Early amyloid‐induced changes in microglia gene expression in male APP/PS1 mice

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid‐beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome‐wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease‐associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from male APPswe/PS1dE9 (APP/PS1) mice and wild‐type littermates were isolated and analyzed by RNA sequencing (RNA‐seq). By bulk RNA‐seq, transcriptomic changes were detected in hippocampal microglia from 6‐months‐old APP/PS1 mice. By performing single‐cell RNA‐seq of CD11c‐positive and negative microglia from 6‐months‐old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c‐positive microglia, we identified a set of genes that potentially reflect the initial response of microglia to Aβ. Single‐cell RNA sequencing of CD11c‐positive microglia from 6‐month‐old APP/PS1 mice uncovered a novel set of genes with the highest expression during the transitional state from homeostatic microglia to disease‐associated microglia (DAMs), suggesting that upregulation of these genes potentially reflects the initial response of microglia to Aβ.