Periodontal bacteria and Alzheimer?s disease

牙周细菌和阿尔茨海默病

• 批准号: 9372139
• 负责人: Kesavalu Naidu Lakshmyya
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372139
• 关键词: Acute-Phase Proteins; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antibodies; Atherosclerosis; Autoimmune Process; Autopsy; Bacteria; Bacterial Translocation; Biology; Brain; Brain Diseases; Cardiovascular system; Cell surface; Cells; Cerebrum; Chronic; Clinical; Clinical Research; Cognitive; Complement; Complement 3 Convertase; Complement Activation; Complex; Data; Dementia; Deposition; Development; Disease; Elderly; Environmental Risk Factor; Etiology; Genes; Genetic; Genomic DNA; Gingiva; Goals; Human; Immune; Immune response; Immune signaling; Immune system; Immunoglobulin G; Immunologic Receptors; Impaired cognition; Impairment; In Vitro; Infection; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory Response; Injectable; Injection of therapeutic agent; Innate Immune Response; Innate Immune System; Interleukin-1 beta; Label; Laboratories; Link; Lipopolysaccharides; Mediating; Membrane; Methods; Microbe; Modeling; Mono-S; Mus; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Oral; Oral cavity; Pathogenesis; Pathologic; Pathology; Patients; Periodontal Diseases; Periodontitis; Peripheral; Plasma; Play; Porphyromonas; Porphyromonas gingivalis; Pre-Clinical Model; Predisposition; Process; Proteins; Reporting; Research; Rheumatoid Arthritis; Risk; Risk Factors; Role; Seeds; Senile Plaques; Serum; Streptococcus gordonii; Systemic disease; TNF gene; Testing; Tissues; Tooth Loss; abeta accumulation; abeta deposition; amyloid formation; antimicrobial peptide; brain tissue; clinical predictors; cytokine; experimental study; genetic risk factor; immune activation; in vivo; interest; microbial; microbiome; mouse model; multidisciplinary; neuroinflammation; neuropathology; neurotoxic; non-demented; oral bacteria; oral microbiome; oral pathogen; oral spirochetes; pathogen; preclinical study; response; tau Proteins

ABSTRACT Alzheimer's disease (AD) is a complex disease of unknown etiologic origin with both environmental and genetic risk factors, contributing to its onset. Systemic and brains local inflammation precedes neurodegenerative processes and predicts clinical onset of AD. Studies suggested that high burden of host inflammation may be responsible for amyloidogenic processes in AD, at least in preclinical models. Fibrillary amyloid β (Aβ) is central to the disease neuropathology, is neurotoxic, and has the capacity to inappropriately activate the innate immune responses including release of cytokines. However, susceptibility to peripheral microbial infections appears to increase during advancing age with the innate immune system becoming inadvertently activated as a disease promoting factor. Periodontal diseases (PD) are among the most common chronic infections of humans, characterized by loss of tooth supporting tissues and caused my complex bacteria underneath the gingiva. Numerous studies link PD associated chronic inflammation with increased risk of dementia, including AD. Plasma levels of antibodies to periodontal bacteria are significantly higher in AD patients compared to non- demented controls. A second study directly demonstrated the presence of multiple different oral bacterial species, causative of periodontal disease, in autopsy brains from AD subjects. We have shown Porphyromonas gingivalis lipopolysaccharide present in 4 out of 10 AD brain tissues and subsequently the innate immune activation as a critical risk factor for developing AD. Following chronic infection of mouse periodontal cavity with P. gingivalis, we could also detect the bacterial genomic DNA and viable bacteria in brains of infected mice. In spite of these findings, the mechanism by which periodontitis may be considered a risk factor for specific pathological hallmark proteins found in AD remains obscure. Despite interesting links between AD and PD and growing evidence that oral bacteria can regulate pathological hallmarks of AD, there is no in vivo study targeting a role for oral bacterium in the initiation of AD. The mechanistic link between chronic inflammation induced by oral bacteria and AD pathology is a high priority for exploration. We hypothesize that chronic systemic inflammation caused by the oral bacterium infection will seed higher Aβ plaque load, and NFT pathology in the TgCRND8 mice and enhance neuroinflammation and neuronal injury. The specific aims are to explore the role of oral bacteria P. gingivalis in regulating A pathology in TgCRND8 AD mouse model. The major objective is to determine the possible causal link between oral bacteria with AD hallmark pathology in vivo. Our long-term goal is to determine how an oral microbe P. gingivalis that can induce systemic effects can influence the development of amyloid and tau pathologies. This is a multidisciplinary project between laboratories that has expertise in periodontal disease research (Dr. Lakshmyya Kesavalu) and neuroinflammatory mechanisms of neurodegenerative diseases (Drs. Todd Golde and Yona Levites).

摘要