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

Patients with Alzheimer's disease (AD) exhibit progressive memory loss, depression, and anxiety, accompa-nied 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, 53FAD and 33Tg-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 acti-vation of ABNs without SuM modification fails to restore behavioral deficits. Furthermore, quantitative phos-phoproteomics analyses reveal activation of the canonical pathways related to synaptic plasticity and micro-glia 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.

Automated summary

Patients with Alzheimer's disease (AD) show memory loss, depression, and anxiety, along with impaired adult hippocampal neurogenesis (AHN). This study demonstrates that optogenetic stimulation of the hypothalamic supramammillary nucleus (SuM) enhances AHN in AD mouse models, improving memory and emotion deficits. Activation of SuM-enhanced adult-born neurons (ABNs) triggers synaptic plasticity and microglia phagocytosis, providing insights into the signaling mechanisms involved.