Oxytocin Intervention Mitigates Pathological and Behavioral Impairments in APP/PS1 Mice Subjected to Early Social Isolation

Abstract

Background: Neuropsychiatric symptoms, such as anxiety and depression, are prevalent during the prodromal phase of Alzheimer's disease (AD). Social isolation (SI) has been implicated as a potential exacerbating factor for emotional disturbances in AD pathogenesis. Despite the well-established role of oxytocin (OXT) in regulating social behavior and mental health, its function and mechanisms in alleviating AD-related psychiatric symptoms remain poorly understood. Materials and Methods: We utilized a 12-week SI model to assess its effects on anxiety, depression-like behaviors, and social cognition in early-stage AD mice. Through immunofluorescence, enzyme-linked immunosorbent assay, and 16S rDNA sequencing, we examined the changes in AD pathology and gut microbiota composition induced by SI, as well as the effects of OXT intervention. Results: Our findings revealed that SI markedly intensified anxiety-like behaviors, depression-like phenotypes, and social cognitive impairments in AD mice. Mechanistically, SI resulted in decreased OXT levels and upregulated OXT receptor expression while also exacerbating AD-related pathological features, including increased Aβ plaque deposition, aberrant microglial proliferation, and reduced PSD-95 expression in the prefrontal cortex. Furthermore, SI induced significant changes in gut microbiota composition. OXT intervention demonstrated therapeutic efficacy by mitigating behavioral deficits, alleviating AD-related pathological damage, and restoring gut microbiota homeostasis in SI AD mice. Conclusion: These results underscore OXT as a promising therapeutic avenue for AD, offering novel insights into treatment strategies and identifying potential therapeutic targets through the restoration of gut homeostasis and mitigation of pathological processes.