CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Neuroscience. 2012 Apr 19;208:85-96. doi: 10.1016/j.neuroscience.2012.02.004. Epub 2012 Feb 9.
We have previously shown that persistent α-synuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) α-synuclein. However, A53T α-synuclein overexpression induced neurodegeneration that resulted in nigral dopaminergic cell death. Here, we analyze the microglia population in the midbrain of these animals by stereological quantification of Iba1+ cells. Our data here show that monkeys overexpressing A53T α-synuclein showed a long-term increase in microglia presenting macrophagic morphology. However, wt α-synuclein overexpression, despite the absence of dopaminergic cell death, resulted in a permanent robust increase of the microglia population characterized by a range of distinct morphological types that persisted after 1 year. These results confirm that the microglial response differs depending on the type of α-synuclein (wt/A53T) and/or whether α-synuclein expression results in cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, the microglial response is modulated by events related to α-synuclein expression in substantia nigra and persists in the long term. The data presented here is in agreement with that previously observed in a recombinant adeno-associated virus (rAAV) α-synuclein rat model, thereby validating both the findings and the model, and highlighting the translational potential of the rodent model to higher species closer to humans.
我们之前已经证明，在狨猴的腹侧中脑中持续过表达α-突触核蛋白会导致独特的神经退行性过程和运动缺陷。在过表达野生型（wt）α-突触核蛋白的动物中，神经退行性变仅限于尾壳核多巴胺能纤维。然而，A53T α-突触核蛋白过表达诱导的神经退行性变导致黑质多巴胺能神经元死亡。在这里，我们通过立体学量化 Iba1+细胞来分析这些动物中脑的小胶质细胞群体。我们的数据显示，过表达 A53T α-突触核蛋白的猴子表现出长期增加的呈现巨噬细胞形态的小胶质细胞。然而，尽管没有多巴胺能神经元死亡，wt α-突触核蛋白过表达导致小胶质细胞群体的永久性强烈增加，其特征是一系列不同的形态类型，在 1 年后仍然存在。这些结果证实，小胶质细胞反应取决于α-突触核蛋白的类型（wt/A53T）和/或α-突触核蛋白表达是否导致细胞死亡，这表明小胶质细胞在疾病进展过程中可能发挥不同的作用。此外，小胶质细胞反应受到与黑质中α-突触核蛋白表达相关的事件的调节，并在长期内持续存在。这里呈现的数据与之前在重组腺相关病毒（rAAV）α-突触核蛋白大鼠模型中观察到的数据一致，从而验证了这些发现和模型，并强调了该啮齿动物模型向更接近人类的高等物种的转化潜力。
