Sex-dependent immune activation shapes disease progression in a model of Parkinson's disease.

BACKGROUND: While it is clear that inflammation contributes to Parkinson's disease (PD) and prevalence is higher in males, sex remains an underexplored determinant of immune responses in PD. METHODS: Using the 3KL transgenic mouse model, which expresses three E to K α-synuclein mutations, we investigated how sex and age shape peripheral and central immunity and behavior in synucleinopathy. Male and female 3KL mice were aged to 8- and 14-months. At these ages animals underwent motor and cognitive assessment, followed by assessment of the peripheral immune response using flow cytometry and analysis of microglial transcriptional profiles by bulk RNA sequencing. RESULTS: Male 3KL mice exhibited earlier onset and greater severity of motor and cognitive impairments, which was linked to a pro-inflammatory peripheral immune profile marked by increased cytotoxic CD8⁺ T cells and IFNγ-producing CD4 Th1 cells. In contrast, female mice displayed delayed symptom onset, preserved cognition, along with early elevations in regulatory IL-10⁺ CD4 and γδ T cells. RNA sequencing of microglia revealed broad sex differences at 8 months. Males demonstrated early upregulation of microglia neurodegenerative signatures, MHC class I/II signaling, ceramide signaling, and pronounced lipid dysregulation, while females showed upregulation of microglial pathways related to protein, metabolic, and neuronal maintenance, including phagosome formation, docosahexaenoic acid signaling, and synaptogenesis pathways. Microglial transcriptional differences were nearly absent by 14 months, suggesting sex-specific trajectories converge during late-stage disease, which is concurrent with a decrease in estrogen in aged female mice. CONCLUSIONS: Together, these findings reveal distinct immune signaling in male and female 3KL mice and identify coordinated changes in T cell and microglial responses that may contribute to sex differences in PD vulnerability and progression. This work underscores the importance of incorporating sex as a biological variable in neurodegeneration research and provides mechanistic insight into immune-mediated modulation of synucleinopathy.