The role of Chlamydia pneumoniae infection in Alzheimer's Disease

肺炎衣原体感染在阿尔茨海默病中的作用

• 批准号: 10631229
• 负责人: Timothy Robert Crother
• 金额: $ 66.28万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631229
• 关键词: Acceleration; Acute; Address; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-42; Amyloid beta-Protein; Antibiotic Therapy; Antibody titer measurement; Antigens; Asthma; Atherosclerosis; Autopsy; Bacteria; Biological Markers; Brain; Cause of Death; Cell model; Chlamydophila pneumoniae; Chronic; Cognition; Data; Data Analyses; Development; Disease; Disease Progression; Early Onset Alzheimer Disease; Economic Burden; Elderly; Emotional; Future; Genetic; Goals; IL17 gene; Immune response; Infection; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Investigation; Late Onset Alzheimer Disease; Link; Location; Long-Term Effects; Lung; Malignant neoplasm of lung; Mediating; Microglia; Mus; Nerve Degeneration; Outcome; Paper; Pathogenesis; Pathogenicity; Pathologic; Pathology; Play; Positioning Attribute; Production; Publishing; Qualifying; Research; Research Personnel; Retina; Role; Senile dementia; Severities; Source; Spatial Distribution; T-Lymphocyte; Testing; Visit; chronic inflammatory disease; community acquired pneumonia; cytokine; mild cognitive impairment; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic microbe; trend

Late onset Alzheimer's Disease (AD), a progressive irreversible senile dementia, is the sixth leading cause of death in the elderly, with an estimated 5.7 million Americans afflicted by this debilitating disorder. These numbers are expected to double in the next 20 years, presenting a significant emotional and economic burden. While AD research continues to be a priority, little headway has been made in slowing disease progression, let alone curing it. Early hypotheses regarding the cause of AD included infectious paradigms, but these ideas were largely discarded as the understanding of the pathogenic role of amyloid β (Aβ) grew and the genetic underpinnings of early onset AD were identified. However, new data has led researchers to once again suggest that infections may play a developmental and/or accelerating role in AD progression. Among infectious organisms, Chlamydia pneumoniae (Cp) has been identified as the leading candidate for a pathogenic role in AD. Cp, a common cause of community-acquired pneumonia, has been linked to many chronic inflammatory diseases, including atherosclerosis, asthma, lung cancer, and AD. In addition to an association between anti-Cp antibody titer and AD, several studies have identified Cp in the brains of AD patients. However, the mechanisms by which Cp infection may alter AD pathogenesis are unknown, and no definitive mouse studies have been performed. Inflammatory cytokines like NLRP3/IL-1β and IL17, both involved in Cp infection induced pathology, may be the key drivers for infection –mediated acceleration of AD, and will be targeted in this application. In a preliminary study we found Cp antigens colocalizing with activated microglia in the brains of Cp infected APPSWE/PS1ΔE9 mice, clearly placing Cp in the right location to influence AD progression. We were also able to identify ASC specks (active inflammasome) in the brains of these mice. Our expertise in Cp infection and immune responses, in combination with our co-PI's expertise in AD, puts us in a uniquely strong position to investigate the relationship between Cp infection and AD, and the potential of antibiotic therapy in Cp-accelerated AD. Based on these data, we hypothesize that Cp infection plays a role in progression and/or development of Alzheimer's Disease, which is preventable by early antibiotic treatment, and that Cp effects are at least partially mediated through activation of the NLRP3 inflammasome and IL-17A. In order to test these hypotheses, we will investigate the following AIMS: 1) Determine the effect of Cp infection on disease progression in APPSWE/PS1∆E9 (ADtg) mice and 2) Determine the role of the NLRP3 inflammasome in Cp infection- modulated AD pathology in ADtg mice and in patients with AD or mild cognitive impairment (MCI) and 3) Determine the role of IL-17A in Cp infection-modulated AD-like pathology in ADtg mice. The completion of our proposal will lay the groundwork for understanding what possible role Cp infection plays in AD. Furthermore, these data will be used as the basis for future research understanding the mechanisms involved Cp infection role in AD with the ultimate goal leading to new therapeutic approaches for this devastating disease.

晚发性阿尔茨海默病（AD）是一种进行性不可逆的老年性痴呆，是阿尔茨海默病的第六大病因。 老年人死亡，估计有570万美国人患有这种使人衰弱的疾病。这些数字 预计在未来20年内将翻一番，带来重大的情感和经济负担。虽然AD 研究仍然是优先事项，在减缓疾病进展方面几乎没有取得进展，更不用说治愈了 了关于AD病因的早期假设包括感染性范例，但这些想法在很大程度上是错误的。 随着对淀粉样蛋白β（Aβ）致病作用的理解的加深和对淀粉样蛋白的遗传基础的认识， 早发型AD。然而，新的数据使研究人员再次表明， 可能在AD进展中起发展和/或加速作用。在传染性微生物中，衣原体 肺炎链球菌（Cp）已被确定为AD中致病作用的主要候选者。CP，一个共同的事业 社区获得性肺炎与许多慢性炎症性疾病有关，包括 动脉粥样硬化、哮喘、肺癌和AD。除了抗Cp抗体滴度与 AD，一些研究已经在AD患者的大脑中鉴定出Cp。然而，CP的机制 感染可能改变AD发病机制是未知的，并且没有进行确定的小鼠研究。 炎症细胞因子如NLRP 3/IL-1β和IL-17，均参与Cp感染诱导的病理，可能是Cp感染诱导的炎症细胞因子。 感染介导的加速AD的关键驱动因素，并将在本申请中作为目标。在初步 我们在感染CP的APPSWE/PS1ΔE9小鼠脑内发现CP抗原与活化的小胶质细胞共定位 小鼠，清楚地将Cp放置在正确的位置以影响AD进展。我们还能识别ASC 这些小鼠大脑中的斑点（活性炎性小体）。我们在Cp感染和免疫反应方面的专业知识， 结合我们的合作PI在AD方面的专业知识，使我们处于一个独特的有利地位，可以调查 Cp感染和AD之间的关系，以及Cp加速AD中抗生素治疗的潜力。根据这些数据， 我们假设Cp感染在阿尔茨海默病的进展和/或发展中起作用， 这是可以预防的早期抗生素治疗，并认为Cp效应至少部分介导 通过激活NLRP 3炎性体和IL-17 A。为了验证这些假设，我们将 研究以下目标：1）确定Cp感染对疾病进展的影响， APPSWE/PS1 β E9（ADtg）小鼠和2）确定NLRP 3炎性体在Cp感染中的作用。 在ADtg小鼠和AD或轻度认知障碍（MCI）患者中调节AD病理学， 3)确定IL-17 A在ADtg小鼠中Cp感染调节的AD样病理学中的作用。完成 我们的建议将奠定基础，了解什么可能的作用Cp感染在AD。 此外，这些数据将被用作未来研究的基础，以了解所涉及的机制 Cp感染在AD中的作用，最终目标是为这种毁灭性疾病提供新的治疗方法。