Infection as a risk factor for dementia: the role of CD36

项目摘要 该提案描述了阿尔茨海默氏症的重点补充R 01研究主机控制机制 抗肺炎克雷伯氏菌感染。在美国， 2020年估计为580万个国家，预计到2040年这一数字将翻一番。感染的作用 阿尔茨海默氏症的发病机制尚不清楚，然而，败血症（严重感染）的幸存者 经历新的认知缺陷，在煽动性侮辱后持续数月至数年。的机制 脓毒症后潜在的认知缺陷尚不清楚。在这个提案中，我们计划研究清道夫的作用 受体CD 36在脓毒症小鼠模型中介导认知下降和阿尔茨海默氏痴呆发病机制。 我们以前的研究主要集中在肺内肺炎克雷伯菌感染后的宿主反应 其中CD 36改善巨噬细胞吞噬功能，减少细菌负荷，并增加存活率。在 与其在宿主反应中的有益作用相反，CD 36在阿尔茨海默氏痴呆中可能是致病的。的 CD 36与淀粉样β蛋白的结合诱导神经炎症和小胶质细胞活化， 临床前模型中的认知缺陷。此外，阿尔茨海默病患者的大脑中CD 36增加 与年龄匹配的对照组相比，CD 36基因多态性与痴呆的发生率增加相关。 阿尔茨海默病的风险。我们假设，虽然CD 36在宿主对感染的反应中是有益的，但CD 36 脓毒症期间的激活诱导持续的神经炎症并由此导致认知下降 加速痴呆的时间，特别是在预先存在淀粉样β沉积的情况下。我们将测试这个 肺内克雷伯菌长期存活小鼠模型中的假设 肺炎感染。我们将研究CD 36在小胶质细胞活化、细胞因子和趋化因子中的作用。 表达、淀粉样蛋白沉积、活性氧生成和认知缺陷的发展 使用雄性和雌性C57 BL/6 J和CD 36-/-小鼠品系在脓毒症后进行。此外，我们将进行研究， 在老年小鼠和具有加速阿尔茨海默氏痴呆表型的小鼠（AppNL-G-F）中， 老年患者和有认知缺陷倾向的患者的败血症。这项提案将是 由匹兹堡大学的一个多学科小组进行，该小组具有宿主对感染的反应方面的专业知识， 脓毒症后的认知缺陷和阿尔茨海默氏痴呆症，并将为未来的研究提供基础 专注于了解感染和痴呆症之间的关系，并预防认知能力下降。

PROJECT ABSTRACT This proposal describes an Alzheimer's focused supplement to an R01 studying host control mechanisms against Klebsiella pneumoniae infection. The number of people living with Alzheimer's dementia in the United States is estimated at 5.8 million in 2020, and this number is expected to double by 2040. The role of infection in Alzheimer's dementia pathogenesis remains unclear, however, survivors of sepsis (severe infections) experience new cognitive deficits that persist for months to years after the inciting insult. The mechanisms underlying cognitive deficits after sepsis are unclear. In this proposal, we plan to study the role of the scavenger receptor CD36 in mediating cognitive decline and Alzheimer's dementia pathogenesis in septic mouse models. Our prior studies have focused on the host response following intrapulmonary Klebsiella pneumoniae infection where CD36 improves macrophage phagocytic function, reduces bacterial burden, and increases survival. In contrast to its beneficial effects in the host response, CD36 may be pathogenic in Alzheimer's dementia. The binding of CD36 to amyloid beta protein induces neuroinflammation and microglial cell activation leading to cognitive deficits in preclinical models. Furthermore, CD36 is increased in the brains of patient's with Alzheimer's dementia compared to age matched controls, and CD36 genetic polymorphisms are associated with increased risk of Alzheimer's disease. We hypothesize that while CD36 is beneficial in the host response to infection, CD36 activation during sepsis induces persistent neuroinflammation and contributes to cognitive decline thereby accelerating time to dementia, particularly in the setting of pre-existing amyloid beta deposits. We will test this hypothesis in an antibiotic-treated mouse model of long-term survival from intrapulmonary Klebsiella pneumoniae infection. We will examine the role of CD36 on microglial activation, cytokine and chemokine expression, amyloid deposition, reactive oxygen species generation, and development of cognitive deficits following sepsis using male and female C57BL/6J and CD36 -/- mice strains. In addition, we will perform studies in aged mice and in mice with an accelerated Alzheimer's dementia phenotype (AppNL-G-F) to model the effects of sepsis on older patients and on patients with predisposition to cognitive deficits. This proposal will be conducted by a multidisciplinary team at the University of Pittsburgh with expertise in host response to infection, cognitive deficits after sepsis, and Alzheimer's dementia, and will provide the foundation for future research focused on understanding relationships between infection and dementia, and preventing cognitive decline.