Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Biomedical Scientist Training Program (Department of Neurosciences), Case Western Reserve University, Cleveland, OH, USA.
Trends Neurosci. 2023 Oct;46(10):814-831. doi: 10.1016/j.tins.2023.07.009. Epub 2023 Aug 24.
Neurodegenerative disorders are characterized by the progressive dysfunction and death of selectively vulnerable neuronal populations, often associated with the accumulation of aggregated host proteins. Sustained brain inflammation and hyperactivation of inflammasome complexes have been increasingly demonstrated to contribute to neurodegenerative disease progression. Here, we review molecular mechanisms leading to inflammasome assembly in neurodegeneration. We focus primarily on four degenerative brain disorders in which inflammasome hyperactivation has been well documented: Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discuss shared and divergent principles of inflammasome assembly across these disorders, and underscore the differences between neurodegeneration-associated inflammasome activation pathways and their peripheral-immune counterparts. We examine how aberrant assembly of inflammasome complexes may amplify pathology in neurodegeneration, including misfolded protein aggregation, and highlight prospects for neurotherapeutic interventions based on targeting inflammasome pathways.
神经退行性疾病的特征是选择性脆弱神经元群体的进行性功能障碍和死亡，通常与聚集的宿主蛋白积累有关。炎症小体复合物的持续脑炎症和过度激活已被越来越多地证明有助于神经退行性疾病的进展。在这里，我们回顾导致神经退行性变中炎症小体组装的分子机制。我们主要集中在四个炎症小体过度激活已被很好地记录在案的退行性脑疾病：阿尔茨海默病（AD）、帕金森病（PD）、多发性硬化症（MS）以及肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的光谱。我们讨论了这些疾病中炎症小体组装的共同和不同原则，并强调了与神经退行性变相关的炎症小体激活途径与其周围免疫对应物之间的差异。我们研究了炎症小体复合物的异常组装如何放大神经退行性变中的病理学，包括错误折叠的蛋白质聚集，并强调了基于靶向炎症小体途径的神经治疗干预的前景。
