Focal microglial activation and progressive dopaminergic neurodegeneration in substantia nigra compacta (SNc) have characterized Parkinson's disease (PD). We have hypothesized that the microglial response may be provoked by molecular signals from chronically stressed SNc neurons. To test whether amyloid precursor protein (APP) could serve as such a signal, we evaluated microglial activation in SN after unilateral transection of the medial forebrain bundle (MFB) in mice either wild-type (WT) or null (KO) for APP. WT and KO mice displayed comparable microglial response at the MFB transection site. In WT mice microglial activation was first apparent in the ipsilateral SN at 3 days postlesion (dpl), marked by morphological change and increased isolectin immunoreactivity. The microglial response intensified at 7 dpl and persisted in the medial nigra through 14 dpl. In contrast, in KO mice activated microglia appeared predominantly at 7 dpl, with little activation at 3 dpl and none at 14 dpl. Neuron number in affected WT SNc at 14 dpl was significantly reduced compared with loss in affected KO SNc. The delayed and limited local microglial activation and increased neuron survival in response to distal axotomy of SNc neurons in APP KO mice are consistent with the important role APP in neuronal stress responses in vivo.

中文翻译：

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APP基因敲除减弱了小胶质细胞的活化，并增强了黑素致密部在轴突切开后的神经元存活。

黑质致密部（SNc）的局灶性小胶质细胞活化和进行性多巴胺能神经退行性变是帕金森氏病（PD）的特征。我们假设小胶质细胞反应可能是由慢性应激的SNc神经元发出的分子信号引起的。为了测试淀粉样蛋白前体蛋白（APP）是否可以作为此类信号，我们评估了野生型（WT）或无效（KO）的小鼠中内侧前脑束（MFB）单侧横切后SN中的小胶质细胞活化。WT和KO小鼠在MFB横切部位显示出类似的小胶质细胞反应。在野生型小鼠中，小胶质细胞活化在患病后3天（dpl）的同侧SN中首先出现，其形态学改变和异凝集素免疫反应性增强。小胶质细胞反应在7 dpl时增强，并一直持续到14 dpl的黑内侧。相反，在KO小鼠中，活化的小胶质细胞主要在7 dpl出现，在3 dpl很少激活，在14 dpl几乎没有激活。与受影响的KO SNc的损失相比，在14 dpl时受影响的WT SNc的神经元数量显着减少。APP KO小鼠对SNc神经元远端轴突切开反应的延迟和有限的局部小胶质细胞活化和增加的神经元存活与APP在体内神经元应激反应中的重要作用相一致。