The impact of Alzheimers Disease neuropathology on immune cell senescence in older African Americans

摘要 本行政补充提案是应NOSI NOT-AG-20-034号文件的要求提交的 与阿尔茨海默氏症相关的研究--与PIs的父母建议“衰老中的免疫细胞衰老的原因”相关 人类。“父母赠款的设计是为了检验这样一种假设，即衰老会导致 人类循环免疫细胞将越来越多地经历端粒功能障碍诱导的细胞 随着年龄的增长而衰老，从而导致与年龄相关的免疫细胞调节失调 功能。原始提案中包含的初步数据显示， 随着年龄的增长，衰老的CD8+T细胞的百分比从大约24%的人 到他们60岁的时候，20岁到大约65%的水平，但有一系列衰老的细胞 不同的捐赠者。积极资助不包括任何与阿尔茨海默氏症有关的研究问题 疾病(AD)。因此，在不改变父母资助目标的情况下，我们寻求补充资金用于 其他方法和参与者招募，以解决在健康的老年人中 被招募的参与者中，一些人可能有较高的AD遗传风险，并可能处于最早阶段 临床前阿尔茨海默病，尽管没有明显的认知缺陷。这是一个意义重大的 担心是因为人们越来越认识到阿尔茨海默病涉及免疫系统的破坏。至 考虑到这种可能性，我们已经与两个备受尊敬的团队和 资金雄厚的AD研究人员。与罗格斯大学的马克·格鲁克-纽瓦克的老龄化和大脑健康 联盟，我们建议再招募32名非洲裔美国人参与者，年龄在60岁及以上，来自 他们在非裔美国人队列中健康老龄化的途径。格鲁克现有队列的庞大规模 允许我们预先选择那些APOE风险最高和最低的人；这些参与者中有一半 将因阿尔茨海默病的高遗传风险而预先选择(APOE基因类型ε4ε4，ε3ε4)，另一半有 阿尔茨海默病的遗传风险低(载脂蛋白E基因型ε2ε2，ε2ε3)。我们还将再招募16名非洲人- 以20岁的S和30岁的S为对照的美国人。他说，第二组新的合作者。 来自哥德堡大学的Blennow和Zetterberg是基于血液的生物标记物方面的专家 早期AD；血浆将被送往这些瑞典合作者，在那里他们将评估基于血液的AD 生物标志物，包括P-Tau181。我们将进行外周免疫细胞衰老的测量 在父母拨款中描述的这些队列中，使用流式细胞术、显微镜和基因组 分析。我们假设处于高APOE基因水平的老年参与者(60岁及以上) 阿尔茨海默病的风险将表现为CD8+T细胞衰老水平的增强，并将增强 CD8+T细胞端粒功能障碍的组织化学证据 AD的载脂蛋白E遗传风险较低，并且将有较高水平的P-Tau181。

Abstract This administrative supplement proposal is submitted in response to NOSI NOT-AG-20-034 to add Alzheimer’s-relevant studies to the PIs’ parent proposal “Causes of Immune Cell Senescence in Aging Humans.” The parent grant was designed to test the hypothesis that aging causes various subsets of human circulating immune cells to increasingly undergo telomere dysfunction-induced cellular senescence with advancing age, thereby resulting in an age-associated dysregulation of immune cell function. Preliminary data included in the original proposal revealed a dramatic and significant increase in the percentages of senescent CD8+ T cells with advanced age, ranging from about 24% in people’s 20s to levels of about 65% by the time they reach their 60s, but with a range of senescent cells across different donors. The active grant does not include any research questions relating to Alzheimer’s Disease (AD). As such, without changing the aims of the parent grant, we seek supplemental funding for additional methods and participant recruitment to address the possibility that, among the healthy older participants recruited, some may have higher genetic risk for AD, and possibly be in the earliest stages of preclinical AD, despite presenting with no readily-apparent cognitive deficits. This is a significant concern because there is a growing appreciation that AD involves disruption to the immune system. To address this possibility, we have entered into new collaborations with two teams of well-respected and well-funded AD-researchers. With Mark Gluck at Rutgers University-Newark’s Aging & Brain Health Alliance, we propose to recruit 32 additional African-American participants, ages 60 and above, from their Pathways to Health Aging in African Americans cohort. The large size of Gluck’s existing cohort allows us to pre-select those individuals with the highest and lowest APOE risk; half of these participants will be pre-selected for high genetic risk for AD (APOE genotypes ε4ε4, ε3ε4), with the other half having low genetic risk for AD (APOE genotypes ε2ε2, ε2ε3). We will also recruit an additional 16 African- American individuals in their 20’s and 30’s as younger controls. A second new set of collaborators, Drs. Blennow and Zetterberg, from the University of Gothenburg, are experts in blood-based biomarkers for early AD; plasma will be sent to these Swedish collaborators where they will assess blood-based AD biomarkers, including P-Tau181. We will carry out measurements of peripheral immune cell senescence in these cohorts as described in the parent grant using flow cytometric, microscopic and genomic analyses. We hypothesize that older participants (ages 60 and above) who are at high APOE-genetic risk for AD will show enhanced levels of senescence in CD8+ T cells and will have enhanced histochemical evidence of telomere dysfunction in their CD8+ T cells as compared to participants who have low APOE-genetic risk for AD, and will have higher levels of P-Tau181.