Hippocampal CA1 neuron, a crucial regulator for chronic stress exacerbating Alzheimer's disease progression.

Chronic stress, a common risk factor for psychiatric disorders, is also implicated in the pathogenesis of Alzheimer's disease (AD). However, its underlying mechanisms remain elusive. Here, we provide evidence for chronic restraint stress (CRS), a widely used stress model in rodents, to regulate AD pathology. CRS not only induces prolonged depressive-like behaviors and cognitive deficits in young adult wild type (WT) mice, but also exacerbates a series of AD-related phenotypes in APP/PS1 mice, including impaired spatial learning and memory, increased β-amyloid plaques, promoted glial cells (astrocyte and microglial cell) activation and decreased dendritic spines in CA1 neurons. Single-nucleus RNA-sequencing analysis in hippocampus shows remarkable transcriptional changes in many cell type(s), and identifies oxidative phosphorylation pathway, a major source for adenosine triphosphate (ATP) production, is significantly downregulated in CA1 neurons by CRS stimuli. Furthermore, dysfunctional mitochondria and reduced ATP levels are also observed in CA1 neurons of CRS exposed WT and APP/PS1 mice. Interestingly, infusion of ATP in CA1 region abolishes the deficits in cognition, dendritic spines and glial activation in CRS exposed APP/PS1 mice. Taken together, these results uncover an unrecognized function of CA1 neurons in regulating CRS induced AD pathologies, and suggest ATP as a promising therapeutic strategy to improve brain health under stress condition.