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).

抽象的 阿尔茨海默病（AD）是一种病因不明的复杂疾病，与环境和遗传因素有关 导致其发生的危险因素 全身和大脑局部炎症发生在神经退行性病变之前。 研究表明宿主炎症的高负担可能是 AD 的过程和预测。 至少在临床前模型中，β-淀粉样蛋白 (Aβ) 是 AD 淀粉样蛋白生成过程的核心。 该疾病的神经病理学具有神经毒性，并且能够不适当地激活先天免疫 然而，对外周微生物感染的易感性似乎与细胞因子的释放有关。 随着年龄的增长，先天免疫系统会被无意中激活为一种疾病 牙周病（PD）是人类最常见的慢性感染之一。 其特点是牙齿支持组织的丧失，并导致牙龈下方出现复杂的细菌。 许多研究将帕金森病相关的慢性炎症与痴呆症（包括 AD）风险增加联系起来。 与非 AD 患者相比，AD 患者血浆中针对牙周细菌的抗体水平明显更高 第二项研究直接证明了多种不同口腔细菌的存在。 我们在 AD 受试者的尸检大脑中发现了导致牙周病的卟啉单胞菌。 牙龈脂多糖存在于 10 个 AD 脑组织中的 4 个中，随后先天免疫 小鼠牙周腔慢性感染后的激活是发生 AD 的关键危险因素。 P. gingivalis，我们还可以检测受感染小鼠大脑中的细菌基因组 DNA 和活细菌。 尽管有这些发现，但牙周炎可能被视为特定危险因素的机制 尽管 AD 和 PD 之间存在有趣的联系，但 AD 中发现的病理标志蛋白仍然不清楚。 越来越多的证据表明口腔细菌可以调节 AD 的病理特征，但尚无针对其的体内研究 口腔细菌在AD引发的慢性炎症中的作用。 口腔细菌和 AD 病理学是我们重点探索的慢性全身性疾病。 口腔细菌感染引起的炎症会导致更高的 Aβ 斑块负载，并且 NFT 病理学 具体目的是探讨TgCRND8对小鼠神经炎症和神经元损伤的增强作用。 口腔细菌牙龈卟啉单胞菌在 TgCRND8 AD 小鼠模型中调节 A 病理学的主要目标是。 确定口腔细菌与 AD 标志性体内病理学之间可能的因果关系。 目标是确定可引起全身效应的口腔微生物牙龈卟啉单胞菌如何影响 淀粉样蛋白和 tau 蛋白病理学的发展是实验室之间的一个多学科项目。 牙周病研究（Lakshmyya Kesavalu 博士）和神经炎症机制方面的专业知识 神经退行性疾病（Todd Golde 博士和 Yona Levites 博士）。