Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

A. M. Schonhoff, D. A. Figge, G. P. Williams, A. Jurkuvenaite, N. J. Gallups, G. M. Childers, J. M. Webster, D. G. Standaert, J. E. Goldman and A. S. Harms ()
Additional contact information
A. M. Schonhoff: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
D. A. Figge: University of Alabama at Birmingham
G. P. Williams: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
A. Jurkuvenaite: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
N. J. Gallups: The University of Alabama at Birmingham
G. M. Childers: The University of Alabama at Birmingham
J. M. Webster: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
D. G. Standaert: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
J. E. Goldman: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
A. S. Harms: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (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-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Date: 2023
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DOI: 10.1038/s41467-023-39060-w

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