Medical School, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
Medical School, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of Education, Nankai University, Tianjin 300071, China.
Brain Res Bull. 2022 Jan;178:120-130. doi: 10.1016/j.brainresbull.2021.11.011. Epub 2021 Nov 25.
In addition to motor dysfunction, cognitive impairments have been reported to occur in patients with early-stage Parkinson's disease (PD). In this study, we examined a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This treatment led to the degeneration of nigrostriatal dopaminergic neurons in mice, a phenomenon that is consistent with previous studies. Besides, spatial memory and object recognition of MPTP-treated mice were impaired, as denoted by the Morris water maze (MWM) and novel object recognition (NOR) tests, respectively. Moreover, hippocampal synaptic plasticity (long-term potentiation and depotentiation) and the levels of synaptic proteins in hippocampus were decreased after MPTP treatment. We also found that MPTP resulted in the microglial activation and an inflammatory response in the striatum and hippocampus. Mammalian asparagine endopeptidase (AEP), a cysteine lysosomal protease, is involved in the cleavage and activation of Toll-like receptors (TLRs). The deletion of AEP can inhibit TLR4 in a mouse model of Alzheimer's disease, and TLR4 is upregulated in PD, inducing microglial activation and inflammation. We found that AEP deletion provided greater resistance to the toxic effects of MPTP. AEP knockout ameliorated the cognition and the synaptic plasticity defects in the hippocampus. Furthermore, AEP deletion decreased the expression of TLR4 and reduced microglial activation and the levels of several proinflammatory cytokines. Thus, we suggest that AEP plays a role in the inflammation induced by MPTP, and TLR4 might also involve in this process. AEP deletion could be a possible treatment strategy for the cognitive deficits of PD.
除了运动功能障碍，早期帕金森病（PD）患者还报告存在认知障碍。在这项研究中，我们检查了由 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型。这种治疗导致小鼠黑质纹状体多巴胺能神经元退化，这与以前的研究一致。此外，MPTP 处理的小鼠的空间记忆和物体识别受损，分别由 Morris 水迷宫（MWM）和新物体识别（NOR）测试表示。此外，海马突触可塑性（长时程增强和去极化）和海马突触蛋白水平在 MPTP 处理后降低。我们还发现，MPTP 导致纹状体和海马中的小胶质细胞激活和炎症反应。哺乳动物天冬酰胺内肽酶（AEP），一种半胱氨酸溶酶体蛋白酶，参与 Toll 样受体（TLR）的切割和激活。在阿尔茨海默病的小鼠模型中，AEP 的缺失可以抑制 TLR4，而 PD 中 TLR4 上调，诱导小胶质细胞激活和炎症。我们发现 AEP 缺失对 MPTP 的毒性作用提供了更大的抵抗力。AEP 敲除改善了海马中的认知和突触可塑性缺陷。此外，AEP 缺失降低了 TLR4 的表达，并减少了小胶质细胞激活和几种促炎细胞因子的水平。因此，我们认为 AEP 在 MPTP 诱导的炎症中起作用，TLR4 也可能参与此过程。AEP 缺失可能是 PD 认知缺陷的一种潜在治疗策略。
