Department of Translational Neuroscience, Michigan State University, 400 Monroe Ave NW, Grand Rapids, MI, 49503, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
J Neuroinflammation. 2024 Apr 25;21(1):108. doi: 10.1186/s12974-024-03108-5.
Parkinson'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.
Male 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.
CSF1R 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.
Collectively, 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.
帕金森病（PD）是一种神经退行性疾病，其特征在于存在蛋白性α-突触核蛋白（α-syn）包涵体（路易体）、神经炎症标志物和黑质纹状体多巴胺（DA）神经元的进行性丧失。这些病理特征可以使用α-syn 预形成纤维（PFF）的突触核蛋白病模型在体内重现。我们之前已经确定，靠近 PFF 诱导的黑质 α-syn 包涵体的小胶质细胞的胞体大小增加，主要组织相容性复合物-II（MHC-II）表达上调，并增加了一系列与炎症相关的转录物的表达。这种小胶质细胞反应在变性前数月就被观察到，这表明对 α-syn 包涵体反应的小胶质细胞可能导致神经退行性变，并且可能成为新疗法的潜在靶点。本研究的目的是确定集落刺激因子-1 受体（CSF1R）介导的小胶质细胞耗竭是否会影响 α-syn 聚集的程度、黑质纹状体变性或 α-syn PFF 模型中小胶质细胞的反应。
雄性 Fischer 344 大鼠通过立体定向注射α-syn PFF 或生理盐水。大鼠连续给予 CSF1R 抑制剂 Pexidartinib（PLX3397B，600mg/kg）以耗尽小胶质细胞，时间为 2 或 6 个月。
CSF1R 抑制导致 SNpc 内离子钙结合接头分子 1 免疫反应性（Iba-1ir）小胶质细胞的显著耗竭（约 43%）。然而，CSF1R 抑制并不影响小胶质细胞数量的增加、胞体大小、MHC-II 免疫反应性小胶质细胞的数量或与磷酸化α-syn（pSyn）黑质包涵体相关的 Cd74、Cxcl10、Rt-1a2、Grn、Csf1r、Tyrobp 和 Fcer1g 的小胶质细胞表达。此外，CSF1R 抑制不影响 pSyn 的积累和黑质神经元的变性。矛盾的是，长期 CSF1R 抑制导致对照和 PFF 大鼠中剩余的 Iba-1ir 小胶质细胞的胞体大小增加，以及外黑质区域 MHC-II 的表达。
总的来说，我们的结果表明 CSF1R 抑制不会影响黑质 pSyn 包涵体中小胶质细胞的反应，并且 CSF1R 抑制不是 PD 的可行疾病修饰策略。
