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IMPORTANCE OF PERIODONTITIS IN THE INNATE IMMUNE REGULATION OF ALZHEIMER'S DISEASE

牙周炎在阿尔茨海默病先天免疫调节中的重要性

基本信息

批准号：
10658447
负责人：
Ping Zhang
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658447
关键词：
Abeta synthesis Acceleration Adult Affect Alveolar Bone Loss Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Brain Cells Central Nervous System Diseases Chronic Classical Complement Pathway Clinical Communicable Diseases Complement Complement 1q Complement Activation Dementia Development Disease Disease Progression Epidemiology Etiology Gene Expression Profile Grant Human Immune Impaired cognition Impairment In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Invaded Knowledge Ligature Link Literature Mediating Microglia Modeling Mus Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neurons Oral Osteitis Pathogenicity Peptide Initiation Factors Periodontal Diseases Periodontal Infection Periodontitis Play Porphyromonas gingivalis Predisposition Prevalence Process Production Reporting Research Role Severities Severity of illness Source Stimulus Synapses Testing Time Tissues Tooth structure Training Wild Type Mouse abeta accumulation age related behavioral impairment chronic infection complement system cytokine effectiveness evaluation glial activation immunoregulation in vivo insight microbial mutant neuroinflammation novel oral infection periodontopathogen preventive intervention response

项目摘要

Project Summary/Abstract Albeit periodontal disease is a local chronic infectious inflammatory process affecting tissues supporting teeth, it can also have systemic consequences. Along these lines are reports that Alzheimer’s disease (AD) is epidemiologically associated with periodontal disease. Yet, the mechanisms underlying this association are not delineated. Our preliminary studies provide new evidence that a keystone periodontal pathogen Porphyromonas gingivalis (Pg) could enter the brain and exacerbate amyloid-b (Ab) accumulation, neuroinflammation, microglia activation, synapse loss, and cognitive and behavioral impairments in AD mice upon oral gavage infection. Microglia are the primary innate immune cells in the brain, and microglial activation is an invariable feature of AD pathology. The complement system also represents a major part of innate immunity, and microglia have been identified as the dominant source of C1q, the initiation factor of the classical complement pathway, in the brain. The objective of this application is to understand the importance of periodontitis in regulating microglial in AD, and the role of complement component C1q in microglial activation and AD progression. Based on the literature and our preliminary results, we hypothesize that periodontal infection and inflammation not only increase the severity of AD, but also increase the risk of AD, via potentiating Ab-primed microglial activation and sensitizing microglia for a heightened inflammatory response to subsequent pathogenic stimuli. In addition, periodontitis-associated persistent C1q activation is critical for microglial priming and activation, and the increased neurodegeneration in AD. We will test our hypothesis by pursuing two specific aims. Aim 1 will determine how periodontitis regulates microglial activation in AD using three different models of periodontitis. Aim 2 will determine the role of complement component C1q in microglial activation and AD development following Pg infection. Our proposed studies will provide novel and significant insights into the association between periodontal infection and AD. Understanding how a prevalent chronic infection like periodontitis modulates complement and microglial activation will advance our understanding of the mysterious etiology of AD. The knowledge obtained from these studies will provide a basis for targeting microbial etiology and periodontal therapy to ameliorate the clinical manifestations of AD and lower AD prevalence.

项目总结/文摘