美国北卡罗莱纳大学Juan Song研究组提出，下丘脑增强的成人海马神经发生(AHN)的激活恢复阿尔茨海默病(AD)的认知和情感功能。2023年4月6日，国际知名学术期刊《细胞—干细胞》发表了这一成果。

他们报道了在两种不同的AD小鼠模型中，下丘脑乳头上核(SuM)的模式光遗传刺激增强了AHN, 5×FAD和3×Tg-AD。引人注目的是，SuM增强的成年出生神经元(ABNs)的化学发生激活挽救了这些AD小鼠的记忆和情感缺陷。相比之下，单纯的SuM刺激或未经SuM修饰的ABN激活均不能恢复行为缺陷。

此外，定量磷蛋白组学分析揭示了与突触可塑性和小胶质细胞吞噬斑块相关的典型通路的激活，在SuM增强的ABN (相对于对照)的急性化学活化后。他们的研究确定了SuM增强的ABN在调节AD相关缺陷方面的活性依赖贡献，并表明由SuM增强的ABNs激活介导的信号机制。·

据介绍，AD患者表现为进行性记忆丧失、抑郁和焦虑，并伴有AHN受损。是否可以在受损的AD大脑中增强AHN以恢复认知和情感功能仍然是一个未知数。

附：英文原文

Title: Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer’s disease

Author: Ya-Dong Li, Yan-Jia Luo, Ling Xie, Dalton S. Tart, Ryan N. Sheehy, Libo Zhang, Leon G. Coleman, Xian Chen, Juan Song

Issue&Volume: 2023/04/06

Abstract: Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether AHN can be enhanced in impaired AD brain to restore cognitive and affective function remains elusive. Here, we report that patterned optogenetic stimulation of the hypothalamic supramammillary nucleus (SuM) enhances AHN in two distinct AD mouse models, 5×FAD and 3×Tg-AD. Strikingly, the chemogenetic activation of SuM-enhanced adult-born neurons (ABNs) rescues memory and emotion deficits in these AD mice. By contrast, SuM stimulation alone or activation of ABNs without SuM modification fails to restore behavioral deficits. Furthermore, quantitative phosphoproteomics analyses reveal activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis of plaques following acute chemogenetic activation of SuM-enhanced (vs. control) ABNs. Our study establishes the activity-dependent contribution of SuM-enhanced ABNs in modulating AD-related deficits and informs signaling mechanisms mediated by the activation of SuM-enhanced ABNs.

DOI: 10.1016/j.stem.2023.02.006

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00043-7