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CSF1R-mediated myeloid cell depletion prolongs lifespan but aggravates distinct motor symptoms in a model of multiple system atrophy

ABSTRACT: As the resident macrophages of the CNS, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they are crucial for de- and regenerative as well as immunological processes. The discovery of distinct activation patterns and increased phagocytosis indicated a damaging role of microglia in multiple system atrophy. This devastating, rapidly progressing atypical parkinsonian disorder is characterized by alpha-synuclein accumulation in the cytoplasm of oligodendrocytes. Alpha-synuclein aggregates have been related to myelin loss, severe neurodegeneration, and motor deficits accompanied by a region-specific myeloid immune response. Analyzing the gene expression profile of microglia in a mouse model of multiple system atrophy, MBP29-hα-syn mice, we identified a disease-assoctiated expression profile with an upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that targeting the CSF1 receptor using the small-molecule inhibitor PLX5622 reduces myeloid cells and thereby modifies the disease progression and neuropathological phenotype in this mouse model. After validation of a widespread depletion of myeloid cells after CSF1R inhibition, we consequently analyzed the survival, motor functions, neuropathological characteristics, and gene expression of affected brain regions in MBP29-hα-syn mice. Intriguingly, we identified a two-faced outcome comprising (1) an improved survival rate (24%) accompanied by delayed onset of neurological symptoms in contrast to (2) severely impaired motor functions in beam walking, pole test, and RotaRod of PLX5622-treated MBP29-hα-syn mice. Gene expression analysis revealed that PLX5622 reversed myeloid cell activation, however, predominantly reduced the expression of genes related to transsynaptic signaling and signal release. While these transcriptional changes were accompanied by a reduction of dopaminergic neurons in the substantia nigra pars compacta (19%) of PLX5622-treated MBP29-hα-syn mice, an increase of the striatal neuritic density was observed without changes in alpha-synuclein levels or myelin lipids in the forebrain. Together, our findings provide insight into the complex role of myeloid cell depletion in multiple system atrophy by demonstrating a two-faced outcome on the behavioral and neuronal phenotype of MBP29-hα-syn mice. Therefore, it is important to carefully balance the beneficial and adversive effects of CSF1R inhibition in different models of neurodegenerative disorders prior to clinical translation.

ORGANISM(S): Mus musculus

PROVIDER: GSE197153 | GEO | 2022/08/01

REPOSITORIES: GEO

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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

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CSF1R-mediated myeloid cell depletion prolongs lifespan but aggravates distinct motor symptoms in a model of multiple system atrophy

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