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: 10381001
• 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/10381001
• 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; Development; Disease; Disease Progression; Economic Burden; Elderly; Emotional; Future; Genetic; Goals; IL17 gene; Immune response; Infection; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-17; 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; Patients; Play; Positioning Attribute; Presenile Alzheimer Dementia; Production; Publishing; Research; Research Personnel; Retina; Role; Senile dementia; Severities; Source; Spatial Distribution; T-Lymphocyte; Testing; base; 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.

晚期发病阿尔茨海默氏病（AD）是一种进行性不可逆转的老年痴呆症，是第六个主要原因 老年人死亡，估计有570万美国人患有这种衰弱的疾病。这些数字 预计未来20年将增加一倍，并带来重大的情感和经济负担。广告时 研究继续是优先事项，在疾病进展的放缓方面几乎没有取得进展，更不用说治愈了 它。关于广告原因的早期假设包括传染性范例，但这些想法在很大程度上是 当理解淀粉样β（Aβ）的致病作用时，被丢弃了 确定了早发广告。但是，新数据已导致研究人员再次提出感染 可能在AD进展中起发育和/或加速作用。在传染性生物中，衣原体 肺炎（CP）已被确定为AD中致病作用的主要候选者。 CP，一个常见原因 在社区获得的肺炎中，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，几项研究已经确定了AD患者的大脑中的CP。但是，CP的机制 感染可能会改变AD发病机理未知，并且没有进行确定的小鼠研究。 参与CP感染诱导病理的NLRP3/IL-1β和IL17等炎性细胞因子可能是 感染的主要驱动因素 - 介导的AD加速度，并将在此应用中针对。在初步 研究我们发现CP抗原与CP感染AppSwe/ps1ΔE9的大脑中的活化小胶质细胞共定位 小鼠显然将CP放置在正确的位置以影响AD的进展。我们也能够识别ASC 这些小鼠的大脑中的斑点（活动性炎症体）。我们在CP感染和免疫反应方面的专业知识， 结合我们的Co-Pi在广告方面的专业知识，使我们处于独特的稳健状态来调查这种关系 在CP感染和AD之间，以及CP加速AD中抗生素治疗的潜力。基于这些数据， 我们假设CP感染在​​阿尔茨海默氏病的进展和/或发展中起作用 早期抗生素治疗可以预防，并且CP效应至少部分介导 通过激活NLRP3炎性体和IL-17A。为了检验这些假设，我们将 研究以下目的：1）确定CP感染对疾病进展的影响 AppSwe/ps1ΔE9（ADTG）小鼠和2）确定NLRP3炎症体在CP感染中的作用 - ADTG小鼠以及AD或轻度认知障碍患者（MCI）和 3）确定IL-17a在CP感染调节ADTG小鼠中的作用。完成 我们的提案将为了解CP感染在​​AD中的作用何种作用奠定基础。 此外，这些数据将被用作将来研究理解所涉及机制的基础 CP感染在​​AD中的作用具有最终目标，从而导致了这种毁灭性疾病的新治疗方法。