Periodontal bacteria and Alzheimer?s disease

摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种病因不明的复杂疾病， 危险因素，促进其发病。全身和大脑局部炎症先于神经退行性变 处理并预测AD的临床发作。研究表明，宿主炎症的高负担可能是 至少在临床前模型中是这样的。纤维状淀粉样蛋白β（Aβ）是 对疾病神经病理学，是神经毒性的，并有能力不适当地激活先天免疫 包括释放细胞因子的反应。然而，对外周微生物感染的易感性似乎 随着年龄的增长，先天免疫系统被无意中激活为疾病， 促进因素牙周病（PD）是人类最常见的慢性感染之一， 特点是牙齿支持组织的丧失，并导致牙龈下的复杂细菌。 许多研究将PD相关的慢性炎症与痴呆症（包括AD）风险增加联系起来。 AD患者牙周细菌抗体的血浆水平显著高于非AD患者。 疯狂的控制。第二项研究直接证明了多种不同的口腔细菌的存在， 种，牙周病的病因，在尸检大脑AD科目。我们已经证明了卟啉单胞菌 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 激活作为发展AD的关键风险因素。慢性感染小鼠牙周膜后， P.此外，我们还可以在感染的小鼠脑中检测细菌基因组DNA和活菌。在 尽管有这些发现，牙周炎可能被认为是特定的危险因素的机制， 在AD中发现的病理标志蛋白仍然不清楚。尽管AD和PD之间存在有趣的联系， 越来越多的证据表明，口腔细菌可以调节AD的病理标志，目前还没有针对AD的体内研究。 口腔细菌在AD发病中的作用。诱导的慢性炎症之间的机制联系 口腔细菌和AD病理学是探索的高度优先事项。我们假设慢性全身性 由口腔细菌感染引起的炎症将导致更高的Aβ斑块负荷， TgCRND8小鼠并增强神经炎症和神经元损伤。具体目的是探讨 口腔细菌牙龈卟啉单胞菌在调节TgCRND8 AD小鼠模型中的AD病理中的作用。主要目标是 以确定口腔细菌与体内AD标志病理学之间可能的因果关系。我们的长期 目的是确定口腔微生物牙龈卟啉单胞菌如何诱导全身效应， 淀粉样蛋白和tau病理学的发展。这是一个实验室之间的多学科项目， 牙周病研究的专业知识（Lakshmyya Kesavalu博士）和神经炎症机制， 神经退行性疾病（托德·戈尔德博士和约纳·莱维特斯博士）。

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).