Unbiased profiling of miR-132 targetome with implications in adult hippocampal neurogenesis and Alzheimer's disease.

Abstract

MicroRNA-132 (miR-132), a potent neuroimmune regulator, is robustly downregulated in the brain of Alzheimer's Disease (AD) patients and its deficiency has been functionally linked to amyloid deposition, TAU hyperphosphorylation and memory decline, in both human and rodents. Of note, miR-132 can explain a higher percentage of the observed variance in histopathological AD phenotypes than APOE e4, a major risk factor for AD. This suggests that miR-132-dependent network-based gene regulation in human AD brain converges onto biological pathways that can drive disease endophenotypes. miR-132 regulates several targets in molecular pathways involved in AD pathophysiology, such as memory formation, neuronal morphogenesis, synaptic plasticity, immune homeostasis, neuronal survival and cell death. Recently, we reported miR-132 as a potent regulator of adult hippocampal neurogenesis (AHN) in healthy and AD brain. Direct miR-132 infusion in the AD mouse brain can counteract several aspects of pathology and memory deficits, suggesting its putative therapeutic relevance. microRNA multi-targeting entails the risk of on- and off- target toxicity, highlighting the importance of systematic genome-wide target validation. While specific miR-132 targets with direct implications in amyloid and TAU pathologies have been previously identified, the complex multicellular miR-132 targetome involved in miR-132-dependent regulation of AHN in AD remains elusive. In order to identify the mechanisms underpinning the positive regulatory effects of miR-132 in AHN and in AD in general, we employed a single-cell RNA-sequencing approach to assess miR-132-specific transcriptomic responses in AHN-relevant cells, such as adult neural stem cells in vivo. We identify novel miR-132 targets with putative neuroimmune functions involved in AHN and possibly in AD pathophysiology. Our results shed light on previously unknown molecular regulators of AHN in brain physiology and AD, provide possible novel therapeutic targets, and further add to the systematic profiling of miR-132 targetome, a prerequisite for successful translation of miR-132 supplementation in AD.