Identify and study the roles of key genes and proteins in subpopulations of Alzheimer's disease patients with uncoupled neurofibrillary tangles

项目摘要 阿尔茨海默病(AD)影响着美国大约10%的65岁及以上的人口，大约40岁 全世界有一百万人。尽管进行了数十年的研究，但阿尔茨海默病的病因仍不清楚， 直到今天，阿尔茨海默病还没有根治的方法。通常，阿尔茨海默病患者的大脑表现出 神经原纤维缠结(NFT)，由与微管相关的聚集束组成 蛋白质tau处于截短或过度磷酸化状态，以及大脑中NFTs的程度通常 与疾病进展、认知功能减退呈正相关。然而，也存在着 疾病轨迹不遵循典型的NFT累积方式的患者亚群。一个 亚组患者的大脑样本显示出类似AD的高NFT，但没有或较低的认知恶化， 而另一亚组患者表现为严重的认知障碍，但NFT病理较低。 研究这些非典型AD亚型，并确定NFT之间这种解偶联的关键因素 病理和认知障碍不仅将提高AD的精准医学水平，而且还将为 关于如何预防和减缓长期疾病期间认知退化的有价值的信息 进步。 在这个项目中，我们的总体假设是转录组、蛋白质组和网络水平 发现非典型NFTs-痴呆非耦合人脑的差异可能有助于 低NFT AD组认知快速恶化机制及痴呆复原力的研究 无症状AD组。我们计划将数据驱动的方法与综合基因组分析相结合 在多个AD蛋白质组和转录组数据集上识别候选基因、蛋白质和 共表达网络在非典型AD的NFTs-痴呆解偶联中起重要作用 病人。已确定的候选基因将在表达的果蝇品系中进一步筛选 人类病理tau基因和蛋白是NTF痴呆的关键因素 解偶联或呈现神经元保护/AD易感性。从以下方面获得有前途的候选人 果蝇的实验将在最早表达人类tau的小鼠品系上进行进一步测试。 在四个月大的时候了解它们在神经元保护或AD易感性方面的作用。我们的长- 学期目标是为进一步申请拨款以阐明NFT-AD提供实验证据 两个亚群背后的解偶联机制，可以为AD开辟新的研究方向 预防以及AD药物的开发。

Project Abstract Alzheimer’s disease (AD) affects about 10% of the US population of age 65 and up, and roughly 40 million people worldwide. Despite decades of studies, the disease etiology of AD still remains unclear, and till today, there is no curative treatment for AD. Typically, AD patient brains show characteristic neurofibrillary tangles (NFTs), which are composed of aggregated bundles of microtubule-associated protein tau in its truncated or hyperphosphorylated state, and the degree of NFTs in the brain usually positively correlates with the disease progression and cognitive decline. However, there also exists subpopulations of patients whose disease trajectories do not follow the typical NFT accumulation way. A subgroup of patients’ brain samples showed AD-like high NFTs but with no or low cognitive deterioration, while another subgroup of patients presents severe cognitive impairment but low NFT pathology. Studying these atypical AD subtypes and identifying key factors in such uncoupling between NFT pathology and cognitive impairment will not only improve precision medicine in AD, but also provide valuable information on how to prevent and slow down cognitive deterioration during the long disease progression. In this project, our overarching hypothesis is that the transcriptomic, proteomic, and network-level differences identified for the atypical NFTs-dementia uncoupled human brains can contribute to the mechanisms of rapid cognitive deterioration in low-NFT AD groups and the dementia resilience in Asymptomatic AD groups. We plan to apply data-driven approaches with integrative genomic analyses on multiple AD proteomic and transcriptomic datasets to identify candidate genes, proteins, and coexpression networks that play important roles in the NFTs-dementia uncoupling in the atypical AD patients. The identified gene candidates will be further screened in the Drosophila strains expressing human pathological tau for causal genes and proteins that are key factors for either NTF-dementia uncoupling or rendering neuron protection/susceptibility to AD. Promising candidates obtained from Drosophila experiments will be further tested in the mouse strains which can express human tau as early as four months old to understand their roles in terms of neuron-protection or AD-susceptibility. Our long- term goal is to generate experimental evidence for further grant applications to elucidate the NFT-AD uncoupling mechanisms behind the two subgroups, which can open new research directions for AD prevention as well as AD drug development.