Protein misfolding is common to neurodegenerative diseases (NDs) including Alzheimer’s disease (AD), which is partly characterized by the self-assembly and accumulation of amyloid-beta in the brain. Lysosomes are a critical component of the proteostasis network required to degrade and recycle material from outside and within the cell and impaired proteostatic mechanisms have been implicated in NDs. We have previously established that toxic amyloid-beta oligomers are endocytosed, accumulate in lysosomes, and disrupt the endo-lysosomal system in neurons. Here, we use pioneering correlative cryo-structured illumination microscopy and cryo-soft X-ray tomography imaging techniques to reconstruct 3D cellular architecture in the native state revealing reduced X-ray density in lysosomes and increased carbon dense vesicles in oligomer treated neurons compared with untreated cells. This work provides unprecedented visual information on the changes to neuronal lysosomes inflicted by amyloid beta oligomers using advanced methods in structural cell biology.

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相关冷冻软 X 射线断层扫描和冷冻结构照明显微镜揭示了β淀粉样蛋白处理的神经元中溶酶体的变化

蛋白质错误折叠在包括阿尔茨海默病 (AD) 在内的神经退行性疾病 (ND) 中很常见，其部分特征是大脑中β-淀粉样蛋白的自组装和积累。溶酶体是降解和回收细胞内外物质所需的蛋白质稳态网络的关键组成部分，ND 中涉及受损的蛋白质稳态机制。我们之前已经确定，有毒的β-淀粉样蛋白寡聚体被内吞，在溶酶体中积累，并破坏神经元中的内溶酶体系统。在这里，我们使用开创性的相关冷冻结构照明显微镜和冷冻软 X 射线断层扫描成像技术来重建天然状态下的 3D 细胞结构，揭示与未经处理的神经元相比，寡聚物处理的神经元中溶酶体中的 X 射线密度降低，碳致密囊泡增加细胞。这项工作利用结构细胞生物学的先进方法，提供了关于淀粉样β寡聚体对神经元溶酶体变化的前所未有的视觉信息。