Differential susceptibility to repeated social stress induces synaptic plasticity impairment and cognitive deficit in the 5xFAD mouse model

Stress-related disorders including depression are common comorbidities in Alzheimer's Disease (AD). In AD, heightened stress reactivity may contribute to an increased risk of cognitive dysfunction. This study aimed to investigate the differential responses of wild-type (WT) and 5xFAD mice, a model of AD, to repeated social defeat stress (RSDS) and explore the molecular mechanisms associated with stress susceptibility. Both WT and 5xFAD mice exhibited susceptibility to initial exposure to RSDS, with a greater proportion of stress-susceptible (Sus) individuals observed in 5xFAD mice compared to WT mice. In presymptomatic 5xFAD mice repeatedly exposed to RSDS, cognitive impairment was evident through a lower discrimination index in the NOR test compared to controls. To investigate the effects of RSDS on peripheral immune responses, we performed CyTOF analysis, revealing a significant increase in CD8 + and CD4 + memory T cells exclusively in the peripheral blood of 5xFAD-Sus mice. To further explore the molecular mechanisms underlying RSDS in the brain, RNA sequencing revealed distinct patterns of differentially expressed genes associated with inflammatory pathways in stress-Sus mice. Specifically, 5xFAD-Sus mice exhibited dysregulation in immune-related pathways, while WT-Sus mice displayed alterations in pathways related to cell adhesion and cytoskeletal organization. In addition, when comparing 5xFAD-Sus to 5xFAD-resilience mice, significant disruptions in synaptic plasticity pathways were observed in 5xFAD-Sus mice, and these changes were accompanied by cognitive impairment. These findings suggest that increased stress susceptibility in 5xFAD is linked to distinct peripheral immune dysregulation, potentially contributing to synaptic plasticity impairments and cognitive dysfunction in the early stages of AD.