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) pa-tients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathol-ogies, 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 ther-apy. 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 dis-ease-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.

Automated summary

miR-132 is significantly downregulated in the brain of Alzheimer's disease patients. Increasing miR-132 levels can improve amyloid and Tau pathologies, as well as restore neurogenesis and memory deficits. However, further analysis is needed to understand the full effects of miR-132 supplementation before it can be used for AD therapy.