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

识别和研究关键基因和蛋白质在具有解偶联神经原纤维缠结的阿尔茨海默病患者亚群中的作用

• 批准号: 10525012
• 负责人: Cristian Lasagna-Reeves
• 金额: $ 42.6万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525012
• 关键词: Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease patient; Applications Grants; Axon; Axonal Transport; Behavioral; Biochemical; Bioinformatics; Biological; Brain; Candidate Disease Gene; Characteristics; Clinical; Cognitive; Data; Data Set; Dementia; Dependovirus; Deposition; Deterioration; Disease; Disease Progression; Disease susceptibility; Drosophila genus; Drosophila melanogaster; Elderly; Etiology; Eye; Gene Proteins; Genes; Genetic Models; Genetic Screening; Genomics; Goals; Human; Impaired cognition; Impairment; Injections; MAPT gene; Measures; Microtubule Bundle; Mining; Mitochondria; Modeling; Mouse Strains; Mus; Neonatal; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Persons; Play; Population; Predisposition; Proteins; Proteomics; Research; Role; Sampling; Screening procedure; Severities; Stress; Subgroup; Synapses; Tauopathies; Testing; Toxic effect; Transgenic Organisms; asymptomatic Alzheimer' s disease; causal variant; curative treatments; differential expression; disorder subtype; drug development; experimental study; fly; human model; improved; in vivo; mouse model; overexpression; patient subsets; precision medicine; prevent; resilience; tau Proteins; tau aggregation; therapeutically effective; transcriptomics

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.

项目摘要 阿尔茨海默氏病（AD）影响了65岁及以上的美国人口的10％，约40％ 全球百万人。尽管进行了数十年的研究，但AD疾病的病因仍然不清楚， 直到今天，还没有治疗AD的治疗方法。通常，广告患者大脑显示出特征 神经纤维缠结（NFTS），由微管相关的聚合束组成 蛋白质tau处于其截短或高磷酸化状态，大脑中的NFT程度通常 与疾病的进展和认知能力下降相关。但是，也存在 疾病轨迹的患者的亚群未遵循典型的NFT积累方式。一个 患者大脑样本的亚组显示出广告样的高NFT，但没有或低认知的定义， 而另一个患者亚组则表现出严重的认知障碍，但NFT病理低。 研究这些非典型AD亚型并识别NFT之间这种解偶联的关键因素 病理和认知障碍不仅会改善广告中的精度医学，还可以提供 关于如何预防和减慢长期疾病期间认知恶化的有价值信息 进展。 在这个项目中，我们的总体假设是转录组，蛋白质组学和网络级别 针对非典型NFTS-诱导未偶联的人类大脑确定的差异可能有助于 低NFT AD组快速认知确定的机制和痴呆症的韧性 不对称广告组。我们计划通过集成基因组分析应用数据驱动的方法 在多个AD蛋白质组学和转录组数据集上，以识别候选基因，蛋白质和 共表达网络在非典型AD中扮演重要角色的重要作用 患者。确定的候选基因将在表达的果蝇菌株中进一步筛选 人类病理tau是因果基因和蛋白质，这是任何一种NTF-诱导的关键因素 解开或渲染神经元保护/对AD的敏感性。从中获得的有希望的候选人 果蝇实验将在小鼠菌株中进一步测试，该菌株可以早期表达人tau 四个月大的时间来理解他们在神经保护或广告抑制性方面的作用。我们的长期 术语目标是为进一步的授予申请生成实验证据，以阐明NFT-AD 两个亚组背后的解偶联机制，可以为AD打开新的研究方向 预防以及AD药物开发。