Neurotoxicology Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Neurobiol Aging. 2012 Mar;33(3):621.e17-33. doi: 10.1016/j.neurobiolaging.2011.02.015. Epub 2011 Apr 11.
In Huntington's disease (HD), mutated huntingtin (mhtt) causes striatal neurodegeneration which is paralleled by elevated microglia cell numbers. In vitro corticostriatal slice and primary neuronal culture models, in which neuronal expression of mhtt fragments drives HD-like neurotoxicity, were employed to examine wild type microglia during both the initiation and progression of neuronal pathology. As neuronal pathology progressed, microglia initially localized in the vicinity of neurons expressing mhtt fragments increased in number, demonstrated morphological evidence of activation, and expressed the proliferation marker, Ki67. These microglia were positioned along irregular neurites, but did not localize with mhtt inclusions nor exacerbate mhtt fragment-induced neurotoxicity. Prior to neuronal pathology, microglia upregulated ionized calcium binding adaptor molecule 1 (Iba1), signaling a functional shift. With neurodegeneration, interleukin-6 and complement component 1q were increased. The results suggest a stimulatory, proliferative signal for microglia present at the onset of mhtt fragment-induced neurodegeneration. Thus, microglia effect a localized inflammatory response to neuronal mhtt expression that may serve to direct microglial removal of dysfunctional neurites or aberrant synapses, as is required for reparative actions in vivo.
在亨廷顿病（HD）中，突变的亨廷顿蛋白（mhtt）导致纹状体神经退行性变，同时伴有小胶质细胞数量的升高。在体外皮质纹状体切片和原代神经元培养模型中，神经元表达 mhtt 片段驱动类似 HD 的神经毒性，用于研究野生型小胶质细胞在神经元病理发生和进展过程中的情况。随着神经元病理的进展，最初定位于表达 mhtt 片段的神经元附近的小胶质细胞数量增加，表现出激活的形态学证据，并表达增殖标志物 Ki67。这些小胶质细胞定位于不规则的神经突附近，但不与 mhtt 包含物定位，也不加剧 mhtt 片段诱导的神经毒性。在神经元病理之前，小胶质细胞上调了离子钙结合衔接分子 1（Iba1），表明功能发生了转变。随着神经退行性变，白细胞介素 6 和补体成分 1q 增加。结果表明，mhtt 片段诱导的神经退行性变起始时存在小胶质细胞的刺激、增殖信号。因此，小胶质细胞对神经元 mhtt 表达产生局部炎症反应，可能有助于小胶质细胞去除功能失调的神经突或异常突触，这是体内修复作用所必需的。
