NACC2 is a molecular effector of miR-132 regulation at the interface between adult neurogenesis and Alzheimer's disease

The process of generating new neurons at the hippocampal neurogenic niche, also referred to as adult hippocampal neurogenesis (AHN), is impaired in Alzheimer's disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target. Overall design: Nestin:GFP+-niche cells were FACS-sorted from the dentate gyrus of Nestin-GFP mice. Four miR-132 antagomir-injected and four control-injected nestin-GFP male mice were used, and 96 cells were initially plated-sorted per mouse (each sample consisted of 1 full dentate gyrus; right and left hemisphere). We then performed gene expression profiling by high throughput sequencing.