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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