Department of Anatomy and Cell Biology, College of Medicine, The University of Illinois at Chicago, Chicago, IL.
Department of Psychiatry, College of Medicine, The University of Illinois at Chicago, Chicago, IL.
J Exp Med. 2022 Sep 5;219(9). doi: 10.1084/jem.20220391. Epub 2022 Aug 19.
Hippocampal neurogenesis is impaired in Alzheimer's disease (AD) patients and familial Alzheimer's disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.
海马神经发生在阿尔茨海默病（AD）患者和家族性阿尔茨海默病（FAD）小鼠模型中受损。然而，目前尚不清楚新神经元是否在记忆缺陷中起因果作用。在这里，我们表明，在海马体依赖性任务后，不成熟的神经元被积极募集到记忆痕迹中。然而，它们在 FAD 中的募集严重不足。募集的不成熟神经元表现出密度降低的刺突和改变的转录谱。在 FAD 小鼠中靶向增加神经发生，可恢复记忆痕迹中新神经元的数量、树突棘密度以及不成熟和成熟神经元的转录特征，最终导致记忆恢复。在 AD 中增强神经发生后，化学遗传失活不成熟神经元可逆转小鼠的表现并减弱记忆。值得注意的是，AD 相关的 App、ApoE 和 Adam10 是记忆痕迹中差异表达基因的前几名。总之，这些观察结果表明，神经发生缺陷导致 AD 中的记忆失败。
