Kanaan Nicholas M, Kordower Jeffrey H, Collier Timothy J
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
Glia. 2008 Aug 15;56(11):1199-214. doi: 10.1002/glia.20690.
Little is known about the effects of aging, the strongest risk factor for Parkinson's disease (PD), on glial responses to dopamine (DA) neuron degeneration in midbrain subregions that display selective vulnerability to degeneration. We evaluated the impact of aging on astrocytes and microglia in a regionally specific manner in a monkey model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was delivered unilaterally via the internal carotid artery of young, middle-aged, and old-aged rhesus monkeys. Astrocytes and microglia were identified using glial fibrillary acidic protein and human leukocyte antigen-DR (HLA-DR) immunolabeling, respectively. Glial reactivity was assessed using (1) stereological cell counting, (2) fluorescence intensity, and (3) a morphology rating scale. In the midbrain contralateral and ipsilateral to the MPTP injection, astrocyte number and intensity did not change with age. In both sides of the midbrain, cellular morphology suggested astrocyte hypertrophy in middle-age dissipated in old-age, irrespective of DA subregion and regional differences in vulnerability to degeneration. In the contralateral midbrain, microglia became mildly activated (increased cell number and intensity, and morphological changes) with advancing age. Inflammation was evident at 3 months postlesion by severe microglial activation in the ipsilateral midbrain. HLA-DR fluorescence intensity and an abundance of activated microglia (based on morphological criteria) were consistently exacerbated in the vtSN of both sides of the midbrain. These results suggest the glial responses accompanying aging and DA neuron degeneration following a toxic insult represent persistent alterations in the microenvironment of surviving DA neurons that are important factors in understanding regional differences in susceptibility to degeneration.
衰老作为帕金森病（PD）最强的风险因素，对中脑亚区域中对变性具有选择性易损性的多巴胺（DA）神经元变性的神经胶质反应的影响鲜为人知。我们在PD的猴子模型中以区域特异性方式评估了衰老对星形胶质细胞和小胶质细胞的影响。通过颈内动脉向年轻、中年和老年恒河猴单侧注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。分别使用胶质纤维酸性蛋白和人类白细胞抗原-DR（HLA-DR）免疫标记来识别星形胶质细胞和小胶质细胞。使用（1）体视学细胞计数、（2）荧光强度和（3）形态学评分量表来评估神经胶质反应性。在MPTP注射对侧和同侧的中脑中，星形胶质细胞数量和强度不随年龄变化。在中脑两侧，无论DA亚区域和变性易损性的区域差异如何，细胞形态学显示中年时星形胶质细胞肥大在老年时消失。在对侧中脑中，小胶质细胞随着年龄的增长而轻度激活（细胞数量和强度增加以及形态变化）。在损伤后3个月，同侧中脑出现严重的小胶质细胞激活，炎症明显。中脑两侧的腹侧被盖区（vtSN）中，HLA-DR荧光强度和大量激活的小胶质细胞（基于形态学标准）持续加剧。这些结果表明，衰老和毒性损伤后DA神经元变性伴随的神经胶质反应代表了存活DA神经元微环境中的持续改变，这是理解变性易感性区域差异的重要因素。
