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

感染作为痴呆症的危险因素：CD36 的作用

基本信息

批准号：
10118704
负责人：
Janet Sojung Lee
金额：
$ 38.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10118704
关键词：
Acute Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid deposition Antibiotics Automobile Driving Bacterial Infections Binding Biological Models Brain CD36 gene Cells Cognitive deficits Complex Data Dementia Deposition Endothelial Cells Female Foundations Generations Genetic Polymorphism Goals Health Care Costs Hospitalization Immune response Impaired cognition Individual Infection Inflammation Klebsiella pneumoniae Laboratories Lipopolysaccharides Lower Respiratory Tract Infection Lung Lung infections Mediating Microglia Modeling Molecular Mouse Strains Mus Older Population Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phagocytes Phenotype Pneumonia Populations at Risk Pre-Clinical Model Predisposition Prevention Reactive Oxygen Species Recovery Research Research Personnel Risk Risk Factors Role Sepsis Survivors Testing Therapeutic Therapeutic Intervention Time United States Universities Work abeta deposition acute infection aged cecal ligation puncture chemokine cognitive development cognitive function combat comorbidity cytokine dementia risk experience improved macrophage male modifiable risk mortality mouse model multidisciplinary neuroinflammation novel older patient pathogen pre-clinical preclinical study prevent public health relevance scavenger receptor septic septic patients

项目摘要

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.

项目摘要该提案描述了阿尔茨海默氏症对R01研究宿主控制机制的重点补充针对肺炎肺炎感染。与阿尔茨海默氏症痴呆症的人数国家估计在2020年为580万，预计到2040年，这一数字将翻一番。感染的作用然而，在阿尔茨海默氏症的痴呆症发病机理中，败血症的幸存者（严重感染）仍不清楚经历新的认知缺陷，这些缺陷在煽动侮辱后持续数月至几年。机制败血症后的潜在认知缺陷尚不清楚。在此提案中，我们计划研究清道夫的作用在化粪池模型中，受体CD36在介导认知下降和阿尔茨海默氏症发病机理中。我们先前的研究集中在肺内肺炎感染后的宿主反应上其中CD36改善了巨噬细胞的吞噬功能，减轻了细菌负担并增加了存活率。在与其在宿主反应中的有益作用相反，CD36在阿尔茨海默氏症的痴呆症中可能是致病性的。这 CD36与淀粉样β蛋白的结合可诱导神经炎症和小胶质细胞激活导致临床前模型中的认知缺陷。此外，Alzheimer的患者大脑中CD36增加了与年龄匹配的对照相比，痴呆症和CD36遗传多态性与增加有关阿尔茨海默氏病的风险。我们假设CD36在宿主对感染的反应中有益，CD36 败血症期间的激活诱导持续的神经炎症，并导致认知能力下降加速痴呆症的时间，特别是在预先存在的淀粉样蛋白β矿床的情况下。我们将测试这个抗生素处理的小鼠模型的假设是肺内克雷伯菌的长期生存的假设肺炎感染。我们将研究CD36在小胶质细胞激活，细胞因子和趋化因子上的作用表达，淀粉样蛋白沉积，活性氧的产生和认知缺陷的发展败血症使用雄性和雌性C57BL/6J和CD36 - / - 小鼠菌株。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症痴呆型表型（APPNL-G-F）的小鼠中，以建模效果老年患者和患有认知缺陷倾向的患者的败血症。该建议将是由匹兹堡大学的跨学科团队进行败血症后的认知缺陷和阿尔茨海默氏症的痴呆症，并将为未来的研究奠定基础专注于理解感染与痴呆之间的关系，并防止认知能力下降。