Neurological disorders such as Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and vascular dementia (VCID) have no disease-modifying treatments to date and now constitute a dementia crisis that affects 5 million in the USA and over 50 million worldwide. The most common pathological hallmark of these age-related neurodegenerative diseases is the accumulation of specific proteins, including amyloid beta (Aβ), tau, α-synuclein (α-syn), TAR DNA-binding protein 43 (TDP43), and repeat-associated non-ATG (RAN) peptides, in the intra- and extracellular spaces of selected brain regions. Whereas it remains controversial whether these accumulations are pathogenic or merely a byproduct of disease, the majority of therapeutic research has focused on clearing protein aggregates. Immunotherapies have garnered particular attention for their ability to target specific protein strains and conformations as well as promote clearance. Immunotherapies can also be neuroprotective: by neutralizing extracellular protein aggregates, they reduce spread, synaptic damage, and neuroinflammation. This review will briefly examine the current state of research in immunotherapies against the 3 most commonly targeted proteins for age-related neurodegenerative disease: Aβ, tau, and α-syn. The discussion will then turn to combinatorial strategies that enhance the effects of immunotherapy against aggregating protein, followed by new potential targets of immunotherapy such as aging-related processes.

中文翻译：

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与衰老相关的神经退行性疾病的免疫疗法——新兴观点和新目标。


阿尔茨海默病 (AD)、路易体痴呆 (LBD)、额颞叶痴呆 (FTD) 和血管性痴呆 (VCID) 等神经系统疾病迄今为止尚无缓解疾病的治疗方法，目前已构成痴呆危机，影响了美国 500 万人全球超过 5000 万。这些与年龄相关的神经退行性疾病最常见的病理特征是特定蛋白质的积累，包括β淀粉样蛋白 (Aβ)、tau、α-突触核蛋白 (α-syn)、TAR DNA 结合蛋白 43 (TDP43) 和重复-相关的非 ATG (RAN) 肽，位于选定大脑区域的细胞内和细胞外空间。尽管这些积累是否是致病性的还是仅仅是疾病的副产品仍然存在争议，但大多数治疗研究都集中在清除蛋白质聚集物上。免疫疗法因其针对特定蛋白质菌株和构象以及促进清除的能力而受到特别关注。免疫疗法还可以起到神经保护作用：通过中和细胞外蛋白质聚集体，它们可以减少扩散、突触损伤和神经炎症。这篇综述将简要探讨针对年龄相关神经退行性疾病 3 种最常见靶蛋白的免疫疗法的研究现状：Aβ、tau 和 α-syn。然后讨论将转向增强免疫疗法针对聚集蛋白的效果的组合策略，然后是免疫疗法的新潜在靶点，例如衰老相关过程。