Department of Neurology, University Medical Center Goettingen, Robert-Koch Str. 40, 37075 Goettingen, Germany.
Department of Neurology, University Medical Center Goettingen, Robert-Koch Str. 40, 37075 Goettingen, Germany; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.
Neurobiol Dis. 2022 Aug;170:105744. doi: 10.1016/j.nbd.2022.105744. Epub 2022 May 2.
Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well. The gut microbiome possibly contributes to inflammatory pathways and shows specific differences in fecal samples from PD compared to healthy controls. In PD, Bacteroides abundance correlates with inflammatory markers in blood and motor impairment. Increased pro-inflammatory and decreased anti-inflammatory bacterial colonization can lead to changes in the metabolic pathways of amino acids, inducing increased membrane permeability, described as a leaky gut, enabling advanced contact between immune cells and gut microbiome and potentially a spreading of neuroinflammation through the body via the blood. Increased cytokine blood levels in PD are correlated with disease severity, motor symptoms, and clinical phenotypes. α-synuclein is a central player in PD-associated inflammation, inducing specific T-cell activity and triggering microglial activation in the central nervous system (CNS). Misfolded α-synuclein propagation possibly results in the spreading of aggregated α-synuclein from neuron to neuron leading to a sustained neuroinflammation. This is supported by age-dependent defects of protein uptake in microglia and monocytes, so-called "inflammaging", including α-synuclein oligomers, as the key pathological protein in PD. Genetic risk markers and inherited forms of PD are also associated with inflammation, which is highly relevant for potential therapeutical targets. The documented associations of inflammatory markers and clinical phenotypes indicate a pro-inflammatory concept of specific PD pathophysiology here. An in-depth understanding of inflammatory mechanisms in PD from bottom (gut) to top (CNS) and vice versa is needed to design novel immunomodulatory approaches to delay or even stop PD. Future studies focusing on structured protocols in large patient cohorts with appropriate control groups and comparative analysis among studies will aid the discovery of novel candidate biomarkers.
帕金森病 (PD) 中的免疫相关改变可以通过评估外周生物体液来监测，这些体液显示特定的炎症途径有助于慢性促炎状态。这种促炎活性被假设已经存在于 PD 的前驱期。这些途径通过刺激细胞激活和增殖来维持和加强慢性神经退行性变，从而引发促炎状态。肠道微生物组可能有助于炎症途径，并在 PD 患者的粪便样本中显示出与健康对照组相比的特定差异。在 PD 中，拟杆菌属的丰度与血液中的炎症标志物和运动障碍相关。促炎和抗炎细菌定植的增加会导致氨基酸代谢途径的变化，导致膜通透性增加，描述为漏肠，使免疫细胞和肠道微生物组之间能够进行更深入的接触，并可能通过血液在体内传播神经炎症。PD 中细胞因子的血液水平升高与疾病严重程度、运动症状和临床表型相关。α-突触核蛋白是 PD 相关炎症的核心参与者，诱导特定的 T 细胞活性，并在中枢神经系统 (CNS) 中触发小胶质细胞激活。错误折叠的α-突触核蛋白的传播可能导致聚集的α-突触核蛋白从神经元传播到神经元，导致持续的神经炎症。这得到了小胶质细胞和单核细胞中依赖年龄的蛋白质摄取缺陷的支持，即所谓的“炎症老化”，包括α-突触核蛋白寡聚体，作为 PD 的关键病理蛋白。遗传风险标志物和遗传性 PD 形式也与炎症相关，这对潜在的治疗靶点非常重要。炎症标志物和临床表型的相关记录表明，这里存在 PD 特定病理生理学的促炎概念。需要从底部（肠道）到顶部（CNS）以及反之对 PD 中的炎症机制进行深入了解，以设计新的免疫调节方法来延迟甚至阻止 PD。未来的研究将集中在具有适当对照组的大型患者队列中的结构化方案和研究之间的比较分析上，这将有助于发现新的候选生物标志物。
