Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA.
Neurobiol Dis. 2022 Sep;171:105804. doi: 10.1016/j.nbd.2022.105804. Epub 2022 Jun 25.
Neuroinflammation has become a well-accepted pathologic hallmark of Parkinson's disease (PD). However, it remains unclear whether inflammation, triggered by α-syn aggregation and/or degeneration, contributes to the progression of the disease. Studies examining neuroinflammation in PD are unable to distinguish between Lewy body-associated inflammation and degeneration-associated inflammation, as both pathologies are present simultaneously. Intrastriatal and intranigral injections of alpha-synuclein (α-syn) preformed fibrils (PFFs) results in two distinct pathologic phases: Phase 1: The accumulation and peak formation of α-syn inclusions in nigrostriatal system and, Phase 2: Protracted dopaminergic neuron degeneration. In this review we summarize the current understanding of neuroinflammation in the α-syn PFF model, leveraging the distinct Phase 1 aggregation phase and Phase 2 degeneration phase to guide our interpretations. Studies consistently demonstrate an association between pathologic α-syn aggregation in the substantia nigra (SN) and activation of the innate immune system. Further, major histocompatibility complex-II (MHC-II) antigen presentation is proportionate to inclusion load. The α-syn aggregation phase is also associated with peripheral and adaptive immune cell infiltration to the SN. These findings suggest that α-syn like aggregates are immunogenic and thus have the potential to contribute to the degenerative process. Studies examining neuroinflammation during the neurodegenerative phase reveal elevated innate, adaptive, and peripheral immune cell markers, however limitations of single time point experimental design hinder interpretations as to whether this neuroinflammation preceded, or was triggered by, nigral degeneration. Longitudinal studies across both the aggregation and degeneration phases of the model suggest that microglial activation (MHC-II) is greater in magnitude during the aggregation phase that precedes degeneration. Overall, the consistency between neuroinflammatory markers in the parkinsonian brain and in the α-syn PFF model, combined with the distinct aggregation and degenerative phases, establishes the utility of this model platform to yield insights into pathologic events that contribute to neuroinflammation and disease progression in PD.
神经炎症已成为帕金森病 (PD) 的一个公认的病理标志。然而，炎症是由α-突触核蛋白聚集和/或变性触发的，这是否会导致疾病的进展尚不清楚。研究 PD 中的神经炎症的研究无法区分路易体相关炎症和变性相关炎症，因为这两种病理同时存在。纹状体和黑质内注射α-突触核蛋白（α-syn）原纤维（PFF）会导致两个不同的病理阶段：第一阶段：α-syn 在黑质纹状体系统中的积累和高峰形成，第二阶段：持续的多巴胺能神经元变性。在这篇综述中，我们总结了α-syn PFF 模型中神经炎症的当前认识，利用明显的第一阶段聚集阶段和第二阶段变性阶段来指导我们的解释。研究一致表明，黑质内病理性 α-syn 聚集与固有免疫系统的激活之间存在关联。此外，主要组织相容性复合物-II（MHC-II）抗原呈递与包含物负荷成比例。α-syn 聚集阶段还与外周和适应性免疫细胞向 SN 的浸润有关。这些发现表明，α-syn 样聚集物是免疫原性的，因此有可能导致退行性过程。研究在神经退行性阶段检查神经炎症时发现固有免疫、适应性免疫和外周免疫细胞标志物升高，但是单一时间点实验设计的局限性阻碍了对这种神经炎症是在黑质变性之前发生还是由其触发的解释。在模型的聚集和变性阶段进行的纵向研究表明，在变性之前的聚集阶段，小胶质细胞激活（MHC-II）的幅度更大。总的来说，帕金森病大脑和α-syn PFF 模型中的神经炎症标志物之间的一致性，加上明显的聚集和变性阶段，确立了该模型平台的实用性，可深入了解导致 PD 中神经炎症和疾病进展的病理事件。
