Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong 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 proneurogenic effects in 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 affected 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 mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.

驻留在海马神经源性生态位中的神经干细胞维持成人大脑中的终生神经发生。成人海马神经发生 (AHN) 在功能上与人类和啮齿动物的记忆和认知可塑性有关。在阿尔茨海默病 (AD) 中，在海马神经源性生态位生成新神经元的过程受到阻碍，但所涉及的机制尚不清楚。在这里，我们确定 miR-132 是 AD 中最一致下调的 microRNA 之一，作为 AHN 的有效调节剂，在成体神经干细胞及其后代中发挥细胞自主神经原性作用。使用不同的 AD 小鼠模型、培养的人类原代和已建立的神经干细胞以及人类患者材料，我们证明 AHN 直接受到 AD 病理学的影响。成年小鼠 AD 海马中的 miR-132 替代物可恢复 AHN 和相关的记忆缺陷。我们的研究结果证实了 AHN 在 AD 小鼠模型中的重要性，并揭示了靶向 miR-132 在神经退行性变中的可能治疗潜力。