Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.
Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.
Neurobiol Dis. 2022 Sep;171:105798. doi: 10.1016/j.nbd.2022.105798. Epub 2022 Jun 21.
The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hmα-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2-3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hmα-SYN-39 mice with wildtype controls. At an age of 16-17 months, however, hmα-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2-3 months transgenic mice and compared to 16-17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4 and CD8 T cell numbers with dopaminergic terminal loss of the striatum was found in hmα-SYN-39 mice, but not in wildtype controls. In the striatum of 16-17 months old wildtype mice a slightly elevated CD8 T cell count and CD11b microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4, CD8 T cell and B220 B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8 T cells, GFAP astrocytes as well as a pronounced increase of CD11b microglia numbers were observed in the SN of hmα-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hmα-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hmα-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.
帕金森病 (PD) 的发病机制与衰老过程密切相关。此外,越来越多的人类尸检研究和 PD 动物模型的证据表明,炎症是疾病发展的另一个因素。我们在这里评估了衰老和炎症对携带人类 A30P/A53T 双突变α-突触核蛋白基因的 hmα-SYN-39 PD 小鼠模型中多巴胺能神经元变性的影响。在 2-3 个月龄时,与野生型对照组相比,hmα-SYN-39 小鼠黑质 (SN) 致密部多巴胺能神经元数量没有显著差异。然而,在 16-17 个月龄时,与年轻的 2-3 个月龄转基因小鼠和 16-17 个月龄野生型同窝小鼠相比,hmα-SYN-39 小鼠显示出明显的多巴胺能 SN 神经元丧失、纹状体多巴胺能末梢丧失以及纹状体多巴胺水平降低。在 hmα-SYN-39 小鼠中,发现浸润的 CD4 和 CD8 T 细胞数量与纹状体多巴胺能末梢丧失呈显著的年龄相关性,但在野生型对照组中没有发现。与年轻的同龄小鼠相比,在 16-17 个月龄野生型小鼠的纹状体中观察到 CD8 T 细胞计数和 CD11b 小胶质细胞计数略有升高。对野生型小鼠黑质纹状体神经炎症的进一步分析没有发现 CD4、CD8 T 细胞和 B220 B 细胞数量有任何显著的年龄依赖性变化。相比之下,在 hmα-SYN-39 小鼠的 SN 中观察到 CD8 T 细胞、GFAP 星形胶质细胞以及 CD11b 小胶质细胞数量的显著年龄依赖性增加,这表明在这种 PD 的遗传小鼠模型中存在神经炎症过程。hmα-SYN-39 小鼠模型的研究结果进一步证实了 T 细胞和神经胶质细胞反应参与了 PD 的年龄相关神经退行性变。在 hmα-SYN-39 PD 啮齿动物模型中,神经退行性变和神经炎症的缓慢和年龄依赖性进展强调了其转化价值,使其适合研究抗炎治疗。
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