Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease
Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease
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DOI：
10.1093/brain/awz363
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发表时间：
2020-01-01
期刊：
影响因子：
14.5
通讯作者：
Green, Kim N.
中科院分区：
文献类型：
--
作者：
Crapser, Joshua D.;Ochaba, Joseph;Green, Kim N.
亨廷顿氏症与反应性小胶质细胞反应和随之而来的脑梗死有关。为了解决这些细胞在疾病发病机制中的规则，我们通过使用培西达替尼（PLX3397）抑制集落刺激因子3受体（CSF1Ri）在疾病持续期间去除R6/2小鼠的小胶质细胞，R6/2小鼠是一种以行为障碍、突变亨廷顿蛋白（mHTT）积累和早期死亡为特征的快速进展的亨廷顿病模型。尽管我们在R6/2小鼠的小胶质细胞形态或细胞因子转录水平中观察到干扰素原，以及与疾病相关的神经生成和突触基因通路下调的特征，但明显的炎症并没有明显的表现。尽管如此，csf1ri诱导的小胶质细胞消除减少或预防了与疾病相关的握力和物体识别缺陷、mHTT积累、星形胶质细胞增生和纹状体体积损失，后者与细胞数量减少无关，但与细胞外accto硫酸盐原聚糖（CSPGs）有关，CSPGs是胶质瘢痕的主要成分。在R6/2小鼠中，蛋白聚糖网的同时丢失也很明显，而小胶质细胞的消除不仅阻止了这种情况的发生，而且还显著增加了幼年幼崽大脑中的神经周围网，这表明小胶质细胞作为神经周围网形成和完整性的稳态调节剂发挥了新的作用。
Huntington's is associated With a reactive microglial response and consequent irlflan nation. To address the rule of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington's disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 3 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gen, signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not eviden by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volum loss, the latter of which was not associated with reductions in cell number but with the extracellular accto sulphate protroglycans (CSPGs)-a primary component of glial scars. A concurrent loss of proteoglycan nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perinettrc nets in the brains of naive littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal perineurcrncll net forrllatior and integriry.