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Sex-dimorphic neuroprotective effect of CD163 in an α-synuclein mouse model of Parkinson’s disease

The aggregation of alpha-synuclein (α-syn) and immune activation are both pathological events related to the neurodegenerative process in Parkinson’s disease (PD). The PD-associated immune response involves both brain and peripheral immune cells, although little is known about the immune proteins relevant for such response. CD163 is a scavenger receptor specifically expressed in the monocytic lineage, but normally not in microglia. Therefore, the presence of CD163 positive cells into the brain in PD rodent models and in PD patients suggest a monocytic infiltration or otherwise ectopic CD163 expression. In addition, changes in CD163 expression profiles observed in PD patients might indicate a role for CD163-expressing cells in the disease. To elucidate the relevance of the CD163 receptor in the α-syn-induced immune events in PD and associated degeneration we injected murine α-syn pre-formed fibrils (PFF), or monomeric α-syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of α-syn PFF in CD163KO females led to impaired early immune responses as revealed by the lack of ability to upregulate MHCII, CD68, GFAP, and promote CD4 and CD8 T cell infiltration after α-syn PFF injection. An early and long-lasting sensorimotor impairment was observed in α-syn PFF CD163KO males but not in the females. Transcriptomic analysis revealed that CD163 deletion induced phenotypic changes of macrophages and microglia in the brain that potentially impact the motor behavior and neuronal health induced by α-syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and α-syn pathology associated with autophagic defects, which ultimately led to increased dopaminergic neurodegeneration. Overall, our results support a novel sex-dimorphic neuroprotective role for CD163 in the α-syn-induced neuropathology and immune response.