Science Division, Yale- NUS College, Singapore, Singapore.
Institute of Molecular and Cell Biology (IMCB), Singapore, Singapore.
Elife. 2020 Mar 31;9:e52589. doi: 10.7554/eLife.52589.
The brains of Alzheimer's disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer's disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use , and to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li treatment. Our results present the first model to separate different aspects of disease progression.
阿尔茨海默病患者的大脑表现出脑质量下降和细胞外淀粉样β斑块增多。这些斑块是由淀粉样前体蛋白（APP）衍生的多肽聚集形成的。淀粉样β斑块被认为在疾病进展中发挥直接或间接作用，然而，淀粉样β肽聚集和斑块形成在阿尔茨海默病（AD）发病机制中的确切作用仍存在争议，因为可溶性和聚集的淀粉样β肽的生物学效应在体内难以分离。为了研究淀粉样β低聚物在活组织中的形成后果，我们开发了一种荧光标记的光遗传淀粉样β肽，在蓝光存在下迅速聚集。我们将该系统应用于一个关键问题，即细胞内淀粉样β低聚物如何构成 A 的病理学基础。我们使用 、 和 表明，尽管淀粉样β的表达和诱导寡聚化对寿命和健康寿命都有不利影响，但我们能够将光诱导的淀粉样β寡聚化引起的代谢和物理损伤与淀粉样β单独表达引起的损伤区分开来。淀粉样β低聚物引起的物理损伤也再现了 AD 晚期的组织大量丢失这一标志性特征。我们表明，用 Li 处理可降低淀粉样β低聚物诱导的寿命缺陷。我们的结果提出了第一个能够分离疾病进展不同方面的模型。
