microRNA-132 regulates adult neural stem cells and their progeny to restore adult hippocampal neurogenesis and memory deficits in Alzheimer's disease

Neural stem cells residing in the hippocampal neurogenic niche sustain life-long neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous pro-neurogenic effects in the adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly impacted by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic significance of targeting miR-132 in neurodegeneration. Overall design: Nestin:GFP+-niche cells were FACS-sorted from the AD dentate gyrus of Nestin:GFP mice at 2 months of age. Four miR-132-injected and four control-injected Nestin:GFP male mice were used and 94 cells were initially sorted per mouse.