Dopaminergic cell loss due to the accumulation of α-syn is a core feature of PD pathogenesis. Neuroinflammation specifically induced by α-syn has been shown to exacerbate neurodegeneration, yet the role of CNS resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-syn related neuroinflammation due to their unique role as the antigen presenting cells necessary

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... initiate a CD4 T cell response. Surprisingly, the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-syn expression led to an expansion in BAM numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that BAMs played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, BAMs were identified in post-mortem PD brain in close proximity to T cells. These results point to a critical role for BAMs in mediating PD pathogenesis through their essential role in the orchestration of the α-syn-mediated neuroinflammatory response.