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

阿尔茨海默病神经病理学对老年非裔美国人免疫细胞衰老的影响

• 批准号: 10287864
• 负责人: PATRICIA FITZGERALD-BOCARSLY
• 金额: $ 23.28万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287864
• 关键词: Address; Administrative Supplement; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Blood; CD8-Positive T-Lymphocytes; Cell Aging; Cell physiology; Cells; Cognitive deficits; Collaborations; Data; Disease susceptibility; Elderly; Functional disorder; Funding; Genetic Risk; Genomics; Genotype; Grant; Health; Health Alliance; Human; Immune; Immune system; Individual; Lead; Leukocytes; Measurement; Methods; Microscopic; Parents; Participant; Pathway interactions; Patient Recruitments; Peripheral; Plasma; Prevention; Research; Research Personnel; Risk; Testing; Time; Universities; base; blood-based biomarker; brain health; cohort; design; early detection biomarkers; neuropathology; parent grant; pre-clinical; recruit; response; senescence; telomere

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.

抽象的 该行政补充提案是针对Nosi Not-AG-20-034提交的，以添加 阿尔茨海默氏症与PIS的父母建议的相关研究“衰老中免疫细胞衰老的原因 人类。”父母的授予旨在检验以下假设，即衰老会导致各种子集 人循环的免疫小球越来越多地接受端粒功能障碍诱导的细胞 随着年龄的增长，感受，从而导致免疫核管的年龄相关失调 功能。原始提案中包含的初步数据显示出急剧增长 在高龄的Senscent CD8+ T细胞的百分比中，人们的范围为24％ 到达60年代时，20秒至约65％的水平，但是有一系列的感觉细胞 不同的捐助者。积极的赠款不包括与阿尔茨海默氏症有关的任何研究问题 疾病（AD）。因此，在不改变父母赠款的目的的情况下，我们寻求补充资金 其他方法和参与者招募，以解决健康较老的可能性 参与者被招募，有些可能对AD的遗传风险更高，并且可能处于最早的阶段 临床前广告，尽管没有明显的认知缺陷。这是重要的 令人担忧的是，人们越来越多地赞赏AD涉及对免疫系统的中断。到 解决这种可能性，我们已经与两个备受尊敬的团队进行了新的合作 资金丰富的广告研究者。马克·格鲁克（Mark Gluck 联盟，我们建议招募32名60岁及以上的非裔美国人参与者 他们在非洲裔美国人队列中卫生衰老的途径。 Gluck现有队列的大尺寸 允许我们预选那些具有最高和最低风险的人；其中一半的参与者 将预先选择AD的高遗传风险（APOE基因型ε4ε4，ε3ε4），另一半具有 AD的低遗传风险（APOE基因型ε2ε2，ε2ε3）。我们还将招募16个非洲 在20年代和30年代，美国人作为年轻控制。第二组新的合作者Drs。 来自哥德堡大学的Blennow和Zetterberg是基于血液的生物标志物的专家 早期广告；等离子体将发送给这些瑞典合作者，他们将评估基于血液的广告 生物标志物，包括P-TAU181。我们将进行周围免疫细胞感应的测量 在这些队列中，如父授予的流式细胞术，微观和基因组中所述 分析。我们假设年龄较大的参与者（60岁及以上年龄）处于高度apoe遗产 AD的风险将显示CD8+ T细胞中的感应水平增强，并将增强 与参与者相比，其CD8+ T细胞中端粒功能障碍的组织化学证据 AD的APOE遗传风险较低，并且P-TAU181的水平较高。