T-cell receptor repertoires and Alzheimer's disease

项目摘要 阿尔茨海默病（AD）是老年人的主要死因，也是经济和健康负担的重要来源。 老人没有治愈AD的方法。随着美国65岁以上成年人的数量在未来几年翻一番， 更好的预防和治疗策略至关重要。流行病学和遗传学研究表明， 几个可修改的（例如，血管健康、教育、身体活动、精神活动，仅举几例）和非 与AD风险相关的可变风险因素。迄今为止确定的晚发性最强的遗传风险因素 AD是APOE e4等位基因。载脂蛋白E调节大脑中的胆固醇，它与淀粉样β肽结合， AD患者中发现的淀粉样斑块的已知主要成分。主要的药物发现工作集中在 淀粉样蛋白β和神经炎症通路的研究，部分基于这些基本的AD发现工作，但没有 已经出现了预防或基本上改变早期糖尿病患者疾病发展轨迹的治疗方法， AD患者。需要新的基础发现研究来更好地理解 AD创造了药物靶点的新途径。 免疫系统反应的变异性是AD发展中的一个新兴因素。AD全基因组 研究反映了与先天性和适应性免疫反应相关的基因的丰富， 进一步表明免疫应答的缺乏导致淀粉样蛋白-β病理学的增加，淀粉样蛋白-β病理学是一种 可以通过骨髓移植来挽救虽然一些基础研究的遗传变异有关， 先天性免疫反应已经进行，迄今为止还没有研究集中在极端的体细胞免疫反应上。 适应性免疫反应的多样性及其与AD的关系。 我们在这里提出，作为AD研究的新研究者，进行一项试点研究，以表征AD患者中的T细胞谱系 Amish AD病例和对照。我们将利用本地AD资源，包括正在进行的AD和成功的 老龄化研究招募了居住在俄亥俄州和印第安纳州的年龄≥80岁的阿米什人。这些资源还包括 来自阵列和下一代测序的现有全基因组数据以及基于整体的插补 基因组测序数据。同样重要的是，本地资源来自积极的AD协作 社区渴望指导和支持新的研究人员锻造原创性的研究， 有助于预防和/或治疗疾病。在这种背景下，我们提出了序列， 30例Amish AD患者和30例对照的T细胞受体β（TCRB）链，以表征TCR多样性及其 可能与AD有关。这些数据将作为适应性免疫的更大研究的关键试点数据。 在未来的和新资助的合作阿米什人和老化记忆项目（CAAMP）的反应，以及 作为未来在不同远系繁殖群体中的研究。

PROJECT SUMMARY Alzheimer’s disease (AD) is a major cause of death and a significant source of financial and health burden among the elderly. There is no cure for AD. With the number of US adults ≥65 doubling in the coming years, the need for better prevention and treatment strategies is paramount. Epidemiologic and genetic studies have identified several modifiable (e.g., vascular health, education, physical activity, mental activity, to name a few) and non- modifiable risk factors associated with AD risk. The strongest genetic risk factor identified to date for late-onset AD is the APOE e4 allele. APOE regulates cholesterol in the brain, and it binds to the amyloid-β peptide, a known major component of amyloid plaques found in AD patients. Major drug discovery efforts have focused on the amyloid-β and neuroinflammation pathways based on, in part, these basic AD discovery efforts, but no therapies have emerged that prevent or substantially change the trajectory of disease development among early AD patients. New basic discovery studies are needed to better understand the etiology and pathophysiology of AD to create new avenues of drug targets. Variability in the immune system’s response is an emerging factor in the development of AD. AD genome-wide studies reflect an enrichment of genes related to the innate and adaptive immune response, and animal models further suggest that the lack of immune response leads to an increase in amyloid-β pathology, a phenotype that can be rescued with bone marrow transplantation. While some basic research on the genetic variants related to the innate immune response has been performed, no research to date has focused on the extreme somatic diversity of the adaptive immune response and its relationship with AD. We propose here as new investigators to AD research a pilot study to characterize the T-cell repertoire among Amish AD cases and controls. We will leverage local AD resources that include ongoing AD and successful aging studies recruiting Amish living in Ohio and Indiana who are ≥80 years old. These resources also include existing genome-wide data from arrays and next-generation sequencing as well as imputation based on whole genome sequencing data. As important, the local resources are drawn from an active AD collaborative community eager to mentor and support new investigators forging original lines of research that potentially contribute to the prevention and/or treatment of disease. Against this backdrop, we propose the sequence the T-cell receptor beta (TCRB) chain of 30 Amish AD cases and 30 controls to characterize TCR diversity and its possible relationship with AD. These data will serve as key pilot data for larger studies of the adaptive immune response in the prospective and newly funded Collaborative Amish & Aging Memory Project (CAAMP) as well as future studies in diverse outbred populations.