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

Schonhoff, A. M.; Figge, D. A.; Williams, Gregory P.; Jurkuvenaite, A.; Gallups, Nicole J; Childers, GM; Webster, John; Standaert, David G.; Goldman, James E.; Harms, Ashley S.

doi:10.1038/s41467-023-39060-w

Cited by 31 publications

(29 citation statements)

References 49 publications

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“…In males, CD163 deletion leads to early increased T-cell infiltration and motor impairment, while in females it may contribute to their higher susceptibility to α-syn PFF and promote increased long-term neurodegeneration. This might be related to changes in the border associated macrophages, which are CD163+ and recently proposed to be crucial mediators of the T-cell infiltration and neurodegeneration in an α-syn PD model 80 . Interestingly, CD163 expression is described in the disease associated microglia (DAM) in AD 25 .…”

Section: Discussionmentioning

confidence: 94%

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

Ferreira

Li²,

Klæstrup

et al. 2022

Preprint

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The aggregation of alpha-synuclein (a-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 a-syn-induced immune events in PD and associated degeneration we injected murine a-syn pre-formed fibrils (PFF), or monomeric a-syn into the striatum of CD163 knockout (KO) mice and wild-type (WT) littermates. Injection of a-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 a-syn PFF injection. An early and long-lasting sensorimotor impairment was observed in a-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 a-syn in a sex-dependent manner. After 6 months, CD163KO females showed an exacerbated immune response and a-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 a-syn-induced neuropathology and immune response.

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Section: Discussionmentioning

confidence: 94%

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

Ferreira

Li²,

Klæstrup

et al. 2022

Preprint

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“…Interesting, at this timepoint reduced CD163-immunoreactivity was found in the lesioned hemisphere by IHC. Expression of CD163 in the brain has been associated with border associated macrophages, which have been identified as the driving cells for immune cell recruitment and infiltration (56). Since we only evaluated CD163 expresssion at 8 weeks, it is possible that we missed a significant increase in this glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Joers,

Murray,

McLaughlin

et al. 2023

Preprint

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There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson’s disease (PD). From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of PD patients and in mice models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration, however CB2 has not been pharmacologically and selectively targeted in an alpha-synuclein focused model of PD. We find that 7 weeks of peripheral SMM-189 treatment reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 altered brain immune cell phenotypes with increased CD68 and decreased CD163 protein expression, elevated wound healing immune mediator gene expression and modified leukocyte infiltration kinetics as determined by flow cytometry. Additionally, peripheral immune cells increased wound healing non-classical monocytes and decreased pro-inflammatory classical monocytes. Together, results suggest that targeting CB2 with SMM-189 biased immune cell function toward a phagocytic phenotype and reduced toxic species of alpha-synuclein aggregation. This study highlights that CB2 may be a target for proteinopathies with notable accompanying inflammation.

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“…snRNA-seq analyses. All analyses were conducted in R using Seurat (v3.1) as previously published (Schonhoff et al, 2023). Briefly, all data underwent quality control filtering any genes expressed in fewer than 3 cells and excluding cells with <300 unique transcripts or more than 3% mitochondrial genes.…”

Section: Methodsmentioning

confidence: 99%

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

Figge,

de Amaral Oliveira,

Crim

et al. 2023

Preprint

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L-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine replacement therapy with L-DOPA for the treatment of Parkinson disease (PD). The emergence of LID is linked to heightened sensitivity of striatal dopaminergic signaling and driven by abnormal fluctuations in synaptic dopamine levels following each administration of L- DOPA. This maladaptive plasticity narrows the therapeutic window for L-DOPA treatment, even as the progressive worsening of PD symptoms demands escalating doses. The heterogeneous composition of the striatum, including diverse subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, has complicated the precise identification of the cell(s) underlying LID development and persistence. To elucidate the cellular and molecular mechanisms of LID, we used single nucleus RNA-sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional profile during the development and maintenance of LID in an animal model. Hemiparkinsonian mice were treated with vehicle or L-DOPA for progressive durations (1, 5, or 10 d) and nuclei from the striata were processed for snRNA-seq. Our analysis found that a limited population of dopamine D1 receptor-expressing MSNs (D1-MSNs), arising from both the patch and matrix compartments, formed three subclusters in response to L-DOPA treatment that expressed cellular markers of activation. These activated D1-MSN subpopulations display many of the transcriptional changes previously associated with LID; however, the prevalence and transcriptional behavior of activated D1-MSNs was differentially influenced by the extent of L-DOPA experience. The differentially expressed genes found in these D1-MSNs indicated that acute L-DOPA induced upregulation of multiple plasticity-related transcription factors and regulators of MAPK signaling, while repeated L-DOPA exposure induced numerous genes associated with synaptic remodeling, learning and memory, and transforming growth factor-ß (TGFß) signaling. Notably, repeated L-DOPA led to a sensitization in the expression ofInhba,a member of the activin/TGFß superfamily, in activated D1-MSNs. We tested pharmacological inhibition of its receptor, ALK4, and found that it impaired LID development. Collectively, these data suggest that distinct subsets of D1-MSNs become differentially responsive to L-DOPA due to the aberrant induction of the molecular mechanisms necessary for neuronal entrainment, similar to those processes underlying hippocampal learning and memory formation. Our data further suggests that activin/TGFß signaling may play an essential role in LID development in this subpopulation of D1-MSNs.

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

Cited by 31 publications

References 49 publications

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

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

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy

Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

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