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: 6374003
• 负责人: ALAN PAUL HUDSON
• 金额: $ 28.25万
• 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/6374003
• 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(摘自申请者摘要)：晚发性阿尔茨海默氏症 疾病(AD)困扰着数百万人，被认为是最严重的 老年痴呆症的重要单一病因。本病无明确定义 目前的病因学，以及引发和 维持致病过程，最终以本病告终仍有待阐明。 然而，已经确定了迟发性阿尔茨海默病的一个危险因素： 拥有载脂蛋白E4等位基因。调查人员证明， 专性细胞内细菌寄生虫肺炎衣原体与 患有晚发性阿尔茨海默病。也就是说，他们显示了受影响的尸检组织 阿尔茨海默病患者的脑区有90%的人是这种微生物的PCR阳性 样本被检查，而几乎没有来自对照大脑的一致组织， 或来自AD患者未受影响脑区的组织也呈类似的阳性。 广泛的电子显微镜，免疫电子显微镜和 阿尔茨海默病和对照大脑的免疫组织化学研究允许可视化 这些样本中的生物体，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细胞几乎位于 仅限于显示阿尔茨海默病相关神经病理的大脑区域。重要的是，在 最近的研究表明，载脂蛋白E4等位基因或其基因 该产品实际上与肺炎衣原体的病理生物学增加有关。在……里面 在本申请中，他们描述了扩展这些挑衅性 初步观察。他们将延长他们对存在的初步研究 以及肺炎衣原体在AD大脑中的位置，更大，更多 临床上明确定义的AD和对照组织集。他们将决定 其他神经退行性疾病是否也有类似的衣原体感染 疾病，它们将定义感染肺炎衣原体之间的关系 细胞/细胞类型与神经病理学的关系。此外，他们将定义贡献 肺炎衣原体对炎症介质产生的影响已知 与AD病理有关，他们将确定C. 肺炎杆菌感染的星形胶质细胞和小胶质细胞有助于生产和 AD脑内异常淀粉样蛋白和PHF-tau的沉积。这项研究 在本申请中提出的将确认肺炎衣原体感染 脑对迟发性AD患者的特异性和分子定义 机体促进/加重疾病的机制。如此新奇 信息很可能为小说的发展提供重要的新见解 预防或改善晚发性阿尔茨海默病的治疗方法。