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 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 Alzheimer's Disease. We use Drosophila, C. elegans and D. rerio 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.

中文翻译：

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光遗传性淀粉样β的应用区分神经变性中的代谢损伤和物理损伤

阿尔茨海默氏病患者的大脑显示出大脑质量下降和大量的细胞外淀粉样β斑块。这些噬菌斑是通过聚集衍生自淀粉样前体蛋白（APP）的多肽而形成的。淀粉样蛋白-β斑块被认为在疾病进展中直接或间接起作用，但是由于可溶性和聚集的淀粉样蛋白-β肽的生物学效应，聚集和斑块形成在阿尔茨海默氏病病因中的确切作用尚有争议。体内难以分离。为了研究在活组织中淀粉样蛋白-β寡聚体形成的后果，我们开发了一种荧光标记的光遗传性淀粉样蛋白-β肽，该肽在蓝光存在下会迅速寡聚。我们将该系统应用于细胞内淀粉样β-寡聚体如何成为阿尔茨海默氏病病理基础的关键问题。我们使用果蝇，秀丽隐杆线虫和里氏D.表明，尽管淀粉样蛋白-β的表达和诱导的寡聚化均不利于寿命和健康期，但我们能够将光诱导的淀粉样蛋白-β寡聚化引起的代谢和物理损伤与淀粉样蛋白-β的表达分开。由淀粉样蛋白-β低聚物引起的物理损伤也概括了灾难性的组织损失，这是晚期AD的标志。我们表明，通过Li ⁺处理可减少淀粉样蛋白-β寡聚物诱导的寿命不足。我们的结果提出了第一个分离疾病进展不同方面的模型。