A closer look at pathogenic amyloid-β in Alzheimer’s disease using cryo-electron microscopy: a narrative review

Alzheimer’s disease is a progressive neurodegenerative disorder that affects millions of people worldwide. The identification of amyloid-β in Alzheimer’s disease brains, together with the association of mutations in the amyloid-β precursor protein with Alzheimer’s disease pathology, is the basis of the amyloid cascade hypothesis, which suggests that amyloid-β plays a central role in Alzheimer’s disease pathogenesis. Recent studies have further highlighted the role of intraneuronal amyloid-β in Alzheimer’s disease development. Moreover, the success of anti-amyloid-β immunotherapies supports the amyloid cascade hypothesis, emphasizing the importance of targeting specific amyloid-β conformations to achieve better therapeutic outcomes. In recent years, cryo-electron microscopy has become an invaluable tool for obtaining near-atomic resolution images of protein assemblies, and multiple structures of brain-derived amyloid fibrils have been elucidated. In this article, we review the role of pathogenic amyloid-β according to the amyloid cascade hypothesis and explore the relationship between intraneuronal amyloid-β accumulation and the development of key pathological features of Alzheimer’s disease—amyloid plaques and neurofibrillary tangles. We also connect cryo-electron microscopy structures of amyloid-β aggregates with amyloid-β-targeting treatment and highlight recent advances and future research directions. The application of cryo-electron microscopy can provide molecular insights into amyloid-β structure, which is expected to help uncover the underlying mechanisms of Alzheimer’s disease and provide new therapeutic strategies for the clearance of amyloid-β aggregates.

摘要

阿尔茨海默病是一种进行性神经退行性疾病，影响着全球数百万人。阿尔茨海默病大脑中淀粉样β蛋白的发现，以及淀粉样β蛋白前体蛋白突变与阿尔茨海默病病理变化的关联，是淀粉样蛋白级联假说的基础，该假说认为淀粉样β蛋白在阿尔茨海默病发病机制中起着核心作用。最近的研究进一步强调了神经元内淀粉样β蛋白在阿尔茨海默病发病过程中的作用。此外，抗淀粉样β蛋白免疫疗法的成功支持了淀粉样蛋白级联假说，强调了靶向特定淀粉样β蛋白构象以获得更好治疗效果的重要性。近年来，冷冻电镜技术已成为获取蛋白质组装体近原子分辨率图像的重要工具，目前已阐明了脑源性淀粉样蛋白纤维的多种结构。文章根据淀粉样蛋白级联假说回顾了致病性淀粉样β蛋白的作用，探讨了神经元内淀粉样β蛋白积累与阿尔茨海默病主要病理特征--淀粉样蛋白斑块和神经纤维缠结--发展之间的关系。文章还将淀粉样β蛋白聚集体的冷冻电镜结构与淀粉样β蛋白靶向治疗联系起来，并重点介绍了最近的研究进展和未来的研究方向。冷冻电镜技术的应用可以从分子角度揭示淀粉样β蛋白结构，有望帮助揭示阿尔茨海默病的内在机制，并为清除淀粉样β蛋白聚集体提供新的治疗策略。