ArticleJournal of neuroinflammation2024
Alpha-synuclein inclusion responsive microglia are resistant to CSF1R inhibition.
Article in Journal of neuroinflammation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 11 citations in OpenAlex.
- The impact of CSF1R inhibitor-mediated microglial depletion in rodent models of Alzheimer's and Parkinson's disease: a systematic review and meta-analysis.Frontiers in aging neuroscience · 2026Pooled it
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- Age-dependent peripheral dissemination of α-synuclein seeds: mechanistic basis for blood-based early detection of Parkinson's disease.Acta neuropathologica communications · 2026Article
- High-dose polystyrene nanoparticles trigger aberrant activation of the MAPK pathway in spinal cord and pain hypersensitivity.Journal of nanobiotechnology · 2026Article
- Parkinson's disease: spatiotemporal regulation and therapeutic prospects of TREM2-mediated microglial responses.NPJ Parkinson's disease · 2026Review
- Engram cell vulnerability in neurodegeneration: from mechanistic insights to therapeutic horizons.Frontiers in aging neuroscience · 2026Review
- Glial-Dopamine crosstalk: Astrocytic and microglial gatekeepers of neuroinflammation, plasticity, and motivation.AIMS neuroscience · 2026Review
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- Single-Cell Transcriptome Analysis of the Retina During the Development of Normal Tension Glaucoma in Mice.Inflammation · 2025Article
- The Endocannabinoid-Microbiota-Neuroimmune Super-System: A Unifying Feedback Architecture for Systems Resilience, Collapse Trajectories, and Precision Feedback Medicine.International journal of molecular sciences · 2025Review
- Intrastriatal injection of alpha-synuclein preformed fibrils to rats results in L-DOPA reversible sensorimotor impairments and alterations in non-motor function.Frontiers in neuroscience · 2025Article
- Experimental and clinical tests of FDA-approved kinase inhibitors for the treatment of neurological disorders (update 2024).Exploration of drug science · 2025Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundParkinson's disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model.
methodsMale Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months.
resultsCSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions.
conclusionsCollectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.
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