Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
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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.
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CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production.
“As immune surveillants, CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production [364,368,371,372,373,374,375,376]”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [375]
The Introduction identifies CAMs as border-associated macrophages (BAMs) and describes BAMs as highly phagocytic. The Results report phagocytosis-related genes and the Discussion supports BAM antigen presentation, but neither establishes that these activities clear harmful substances. The Discussion links BAM-mediated T-cell restimulation to local cytokine production; it does not establish cytokine production by CAMs as a clearance mechanism. Page numbers were not provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMHCII+ BAMs are implicated in neurodegeneration, for example by initiating α-synuclein-mediated neuroinflammatory responses through restimulation of CD4+ T-cells.
“MHCII+ BAMs are also implicated in neurodegeneration, for example by initiating α-synuclein-mediated neuroinflammatory responses through restimulation of CD4+ T-cells.55”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [55]
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- Authors
- Schonhoff, A. M., Figge, D. A., Williams, G. P., Jurkuvenaite, A., Gallups, N. J., Childers, G. M., Webster, J. M., Standaert, D. G., Goldman, J. E., & Harms, A. S.
- Affiliations
- University of Alabama at Birmingham (US)
- Aligning Science Across Parkinson's (US)
- Corresponding author
- Harms, A. S.
- ORCID
- Venue
- Nature Communications
- Published
- 2023-06-26
- Volume
- 14
- Issue
- 1
- Pages
- 3754-3754
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10293214
- OpenAlex
- W4382059965
- Cited by
- 161
- References
- 14
- Citations by year
- 2026: 52 · 2025: 50 · 2024: 45 · 2023: 13 · 2022: 1
- FWCI
- 16.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (5 F31 NS106722-02, R01NS107316)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- border-associated macrophages, Parkinson's disease, alpha-synuclein, neuroinflammation, antigen presentation, CD4+ T cells, microglia, MHC class II, dopaminergic neuron loss, immune cell recruitment, T cell infiltration, single-cell RNA sequencing, mouse model
- MeSH terms
- Neuroinflammatory Diseases, Humans, Inflammation, Macrophages, Parkinson Disease, Microglia, alpha-Synuclein
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