CHLAMYDIA PNEUMONIAE--A PATHOGEN IN ALZHEIMERS DISEASE

肺炎衣原体——阿尔茨海默病的病原体

• 批准号: 2901888
• 负责人: ALAN PAUL HUDSON
• 金额: $ 28.69万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2901888
• 关键词: Alzheimer's disease; Chlamydiaceae; clinical research; cytokine; disease /disorder etiology; disease /disorder onset; electron microscopy; glia; human subject; immunocytochemistry; microglia; molecular pathology; neuropathology; polymerase chain reaction; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): Late-onset Alzheimer's disease (AD) afflicts millions of individuals and is thought to be the most important single cause of senile dementia. This disease has no clearly defined etiology at the present time, and the detailed events that initiate and maintain the pathogenic process ending in the disease remain to be elucidated. However, one risk factor for development of late-onset AD has been identified: possession of the APOE E4 allele. The investigators demonstrated that the obligate intracellular bacterial parasite Chlamydia pneumoniae is associated with late-onset AD. That is, they showed that autopsy tissues from affected brain regions of AD patients are PCR-positive for the organism in 90% of samples examined, whereas virtually no congruent tissues from control brains, or tissues from unaffected brain areas of AD patients, were similarly positive. Extensive electron microscopic, immunoelectron microscopic and immunohistochemical study of AD and control brains allowed visualization of the organism in these samples, definition of host cells as microglia and astroglia, and provided clear evidence that chlamydia-infected cells are located almost exclusively in brain regions showing AD related neuropathology. Importantly, in more recent studies they demonstrated that the APOE E4 allele or its gene product is actually associated with increased pathobiology of C pneumoniae. In the present application, they describe studies to extend these provocative initial observations. They will extend their initial studies of the presence and location of C. pneumoniae in the AD brain in another, larger, and more clinically well defined set of AD and control tissues. They will determine whether similar chlamydial infection obtains in other neurodegenerative diseases, and they will define the relationship between C. pneumoniae infected cells/cell types to neuropathology. Further, they will define the contribution of C. pneumoniae to the production of inflammatory mediators known to be associated with AD pathology, and they will determine whether C. pneumoniae-infected astroglia and microglia contribute to production and deposition of aberrant amyloid and PHF-tau in the AD brain. The research proposed in this application will confirm that C pneumoniae infection of the brain is specific to patients with late-onset AD and define molecular mechanisms by which the organism promotes/exacerbates the disease. Such new information may well provide important new insights for development of novel therapeutic modalities to prevent or ameliorate late-onset AD.

描述（改编自申请人的摘要）：迟发性阿尔茨海默病 疾病（AD）折磨着数百万人，被认为是最严重的疾病。 老年痴呆症的重要单一病因。这种疾病没有明确的定义。 目前的病因学，以及引发和 保持致病过程结束的疾病仍有待阐明。 然而，已经确定了迟发性AD发展的一个风险因素： 携带APOE E4等位基因研究人员证明， 专性细胞内细菌寄生虫肺炎衣原体与 晚发性AD也就是说，他们发现， AD患者的大脑区域中90%的生物体为PCR阳性， 检查样本，而对照组大脑几乎没有相同的组织， 或来自AD患者的未受影响的脑区域的组织也是类似的阳性。 广泛的电子显微镜，免疫电镜和 对AD和对照组大脑的免疫组织化学研究显示， 这些样品中的生物体，将宿主细胞定义为小胶质细胞和星形胶质细胞， 并提供了明确的证据表明，衣原体感染的细胞几乎位于 仅在显示AD相关神经病理学的脑区域中。重要的是在 最近的研究表明，APOE E4等位基因或其基因 产品实际上与肺炎衣原体的病理生物学增加有关。在 在本申请中，他们描述了将这些刺激性研究 初步意见。他们将扩大他们的初步研究的存在 和C.肺炎在AD脑中的另一个，更大，更 临床上明确定义的AD和对照组织组。他们将决定 是否在其他神经退行性疾病中获得类似的衣原体感染 疾病，他们将定义C.肺炎感染 细胞/细胞类型的神经病理学。此外，他们将定义贡献 梭肺炎的炎症介质的生产已知是 与AD病理学相关，他们将确定C. 肺炎感染的星形胶质细胞和小胶质细胞有助于生产， AD脑中异常淀粉样蛋白和PHF-tau的沉积。研究 本申请中提出的方法将证实， 大脑是特异性的晚发性AD患者和定义分子 生物体促进/加重疾病的机制。这种新 信息可以为小说发展提供重要的新见解 预防或改善迟发性AD的治疗方式。