microRNA-132 regulates gene expression programs involved in microglial homeostasis

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells. Overall design: Cells from the right hippocampus of mice treated with miR-132 antagomiR/scrambled control and miR-132 mimic/negative control were isolated by Fluorescence-activated cell sorting (FACS) based on viability (e780, replicates 1 and 3) and in addition for the presence or absence of YFP signal (neurons) or CD11b and ACSA-2 (astrocytes) (replicates 2, 4 and 5) and analyzed using scRNAseq.