Periodontal bacteria and Alzheimer?s disease

摘要 阿尔茨海默病(AD)是一种病因不明的复杂疾病，既有环境因素也有遗传因素 风险因素，促成了它的发病。全身和大脑局部炎症先于神经退行性变 处理和预测阿尔茨海默病的临床发作。研究表明，宿主炎症的高负担可能是 负责AD的淀粉样变过程，至少在临床前模型中是这样。纤维淀粉样蛋白β(Aβ)是中枢 对疾病的神经病理，是神经毒性的，并有能力不适当地激活先天免疫 反应包括细胞因子的释放。然而，对外周微生物感染的易感性似乎 随着年龄的增长，与生俱来的免疫系统会被不经意地激活为一种疾病 促进因素。牙周病(PD)是人类最常见的慢性感染之一， 以牙齿支持组织的丧失为特征，并导致我的牙龈下的复杂细菌。 许多研究将帕金森病与慢性炎症联系在一起，增加了患痴呆症的风险，包括AD。 AD患者血浆抗牙周细菌抗体水平显著高于非AD患者 精神错乱的控制力。第二项研究直接证明了多种不同口腔细菌的存在。 阿尔茨海默病患者尸检脑组织中牙周病的致病物质。我们已经向人们展示了卟啉单胞菌 牙周菌脂多糖存在于10个AD脑组织中的4个，继而是先天免疫 激活是阿尔茨海默病的关键风险因素。小鼠牙周炎慢性感染后的牙周炎 我们还可以在感染小鼠的脑内检测到细菌基因组DNA和活菌。在……里面 尽管有这些发现，牙周炎可能被认为是特定疾病的危险因素的机制 在AD中发现的病理标志蛋白仍不清楚。尽管AD和PD之间有有趣的联系， 越来越多的证据表明口腔细菌可以调节AD的病理特征，目前还没有针对体内的研究 口腔细菌在阿尔茨海默病发病中的作用。黄曲霉毒素所致慢性炎症的机制联系 口腔细菌和AD的病理学是一个高度优先探讨的问题。我们假设慢性系统性疾病 口腔细菌感染引起的炎症会导致较高的Aβ斑块负荷，并导致NFT病理改变 TgCRND8小鼠，并增强神经炎症和神经元损伤。其具体目的是探索其角色 口腔细菌牙龈假单胞菌对TgCRND8AD小鼠模型A-病理的调节作用主要目标是 目的：确定口腔细菌与体内AD标志性病理之间可能的因果联系。我们的长期合作 目标是确定一种能够引起全身影响的口腔微生物牙龈假单胞菌如何影响 淀粉样蛋白和tau病理的发展。这是一个多学科的项目，实验室之间有 牙周病研究的专门知识(Lakshmyya Kesavalu博士)和神经炎性机制 神经退行性疾病(托德·戈尔德博士和约娜·莱维茨博士)。

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).