Understanding Amyloid Post-Translational Modification at the Nanoscale

阿尔茨海默病是一种致命的、无法治愈的痴呆症，影响着全球5000万人。尽管阿尔茨海默病的发病率很高，但目前还没有治愈或生物特征诊断测试。淀粉样β-多肽的小聚集体，称为寡聚体，在阿尔茨海默病中引起毒性，并与疾病的发生和发展有关。越来越多的证据表明，翻译后修饰改变了淀粉样β蛋白聚集的倾向。然而，目前还没有关于这种修饰对低聚物结构和机理的影响的信息，因为低聚物太不均匀和稀疏，不能用标准方法研究。为了克服这一挑战，我们将提供一个新的分析平台，在单分子水平上研究低聚物。我们将结合通过定量聚合酶链式反应(QPCR)进行的超敏抗体检测、超分辨显微镜和合理的药物设计来确定病理翻译后修饰如何影响淀粉样β蛋白寡聚体的结构、毒性和可药性。我们的结果将为阿尔茨海默病的关键机制提供前所未有的信息，并开启新的临床干预措施。

Alzheimer's disease is a fatal and incurable form of dementia, affecting 50 million people worldwide. Despite the high prevalence of Alzheimer's disease, currently, there is no cure or biometric diagnostic test for it. Small aggregates of the amyloid-beta peptide, called oligomers, cause toxicity in Alzheimer's disease, and are associated with the disease's onset and progression. Increasing evidence suggest that post-translational modifications alter the propensity of amyloid-beta to aggregate. However, there is currently no information on the implication of such modifications for oligomers' structure and mechanisms, as oligomers are too heterogenous and sparse to be studied with standard methods. To overcome this challenge, we will deliver a novel analytical platform to study oligomers at the single-molecule level. We will combine ultra-sensitive antibody detection via quantitative Polymerase Chain Reaction (qPCR) with super-resolution microscopy and rational drug design to determine how pathological post-translational modifications affect the structure, the toxicity and the druggability of amyloid-beta oligomers. Our results will provide unprecedented information on key mechanisms of Alzheimer's disease and open new clinical intervention.