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）影响约10%的美国65岁及以上人口，约40 全球百万人。尽管经过几十年的研究，AD的病因仍然不清楚， 直到今天，还没有治愈AD的治疗方法。通常，AD患者的大脑表现出特征性的 神经纤维缠结（NFT），由聚集的微管相关神经纤维束组成。 蛋白质tau在其截短或过度磷酸化状态，以及脑中NFT的程度通常 与疾病进展和认知能力下降正相关。然而， 疾病轨迹不遵循典型NFT累积方式的患者亚群。一 患者脑样本亚组显示AD样高NFT，但没有或低认知恶化， 而另一个亚组的患者表现出严重的认知障碍，但NFT病理学较低。 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 病理学和认知障碍不仅将改善AD的精准医学， 关于如何在长期疾病期间预防和减缓认知恶化的宝贵信息 进展 在这个项目中，我们的首要假设是转录组学、蛋白质组学和网络水平 非典型NFTs-dementia非耦合人脑的差异可能有助于 低NFT AD组的快速认知恶化机制和 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蛋白质组学和转录组学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NFT-痴呆解偶联中发挥重要作用 患者鉴定的候选基因将在表达以下基因的果蝇品系中进一步筛选： 人类病理性tau蛋白的致病基因和蛋白质是NTF-痴呆或 解偶联或使神经元保护/对AD易感。有希望的候选人从 果蝇实验将在小鼠品系中进行进一步测试，这些小鼠品系可以尽早表达人类tau蛋白。 以了解它们在神经元保护或AD易感性方面的作用。我们长久以来- 一个学期的目标是为进一步的资助申请提供实验证据，以阐明NFT-AD 这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.