Augmenting neurogenesis rescues memory impairments in Alzheimer's disease by restoring the memory-storing neurons.
Augmenting neurogenesis rescues memory impairments in Alzheimer's disease by restoring the memory-storing neurons.
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DOI：
10.1084/jem.20220391
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发表时间：
2022-09-05
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海马神经发生缺陷通过损害记忆储存导致阿尔茨海默病的认知障碍。增强神经发生通过招募更多具有恢复的棘密度和转录谱的新神经元来拯救记忆。与AD相关的基因调节记忆储存神经元。阿尔茨海默病（AD）患者和家族性阿尔茨海默病（FAD）小鼠模型的海马神经发生受损。然而，尚不清楚新的神经元是否在记忆缺陷中发挥了致病作用。在这里，我们表明，未成熟的神经元被积极招募到记忆印迹后，一个依赖于海马区的任务。然而，第一志愿军招募工作严重不足。招募的未成熟神经元表现出受损的棘密度和改变的转录谱。FAD小鼠神经发生的靶向增强恢复了记忆印迹中新神经元的数量、树突棘密度以及未成熟和成熟神经元的转录特征，最终导致记忆的拯救。在AD中增强神经发生后未成熟神经元的化学发生失活，逆转了小鼠的表现，并减少了记忆。值得注意的是，AD相关App、ApoE和Adam10是印迹中差异表达最高的基因。总的来说，这些观察结果表明，神经发生缺陷导致AD的记忆障碍。
Deficits in hippocampal neurogenesis cause cognitive impairments in Alzheimer’s disease by compromising memory storage. Augmenting neurogenesis rescues memory by recruiting more new neurons with restored spine density and transcription profile. AD-linked genes regulate the memory-storing neurons. 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.
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影响因子：
11
作者：
Bartolotti N;Bennett DA;Lazarov O
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影响因子：
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