The role of Chlamydia pneumoniae infection in Alzheimer's Disease

迟发性阿尔茨海默病(AD)是一种进行性不可逆转的老年性痴呆，是导致老年性痴呆的第六大原因 老年人死亡，估计有570万美国人患有这种令人衰弱的疾病。这些数字 预计在未来20年将翻一番，这将带来巨大的情感和经济负担。而AD 研究仍然是优先事项，在减缓疾病进展方面进展甚微，更不用说治愈了 它。早期关于阿尔茨海默病病因的假设包括传染性范式，但这些想法在很大程度上是 随着对淀粉样蛋白β(Aβ)致病作用的了解不断增长，以及 确诊为早发性阿尔茨海默病。然而，新的数据使研究人员再次表明，感染 可能在AD进展中起发展和/或加速作用。在感染性生物中，衣原体 肺炎杆菌(CP)已被确定为AD的主要致病因素。CP，一项共同的事业 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、肺癌和阿尔茨海默病。除了抗CP抗体效价和 AD，几项研究已经确定了AD患者大脑中的CP。然而，CP的作用机制 感染可能改变AD的发病机制尚不清楚，也没有进行明确的小鼠研究。 炎性细胞因子如NLRP3/IL-1β和IL17都参与了CP感染诱导的病理过程，可能是 感染介导的AD加速的关键驱动因素，并将在此应用程序中作为目标。在预赛中 研究发现，在CP感染的APPsWE/PS1ΔE9的脑组织中，CP抗原与激活的小胶质细胞共存 小鼠，显然将CP放置在正确的位置以影响AD的进展。我们还能够识别出ASC 这些小鼠大脑中的斑点(活动性炎症体)。我们在CP感染和免疫反应方面的专业知识， 再加上我们在AD方面的专业知识，使我们在调查关系方面处于独特的有利地位 CP感染与AD之间的关系，以及CP加速AD的抗生素治疗的可能性。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， 这是可以通过早期抗生素治疗来预防的，而且CP效应至少是部分介导的 通过激活NLRP3炎症体和IL-17A。为了检验这些假设，我们将 调查以下目的：1)确定肺炎衣原体感染对疾病进展的影响 APPsWE/PS1∆E9(ADtg)小鼠和2)确定NLRP3炎症体在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 3)探讨IL-17A在CP感染诱导的ADtg小鼠AD样病变中的作用。完成度 我们的建议将为了解CP感染在AD中可能发挥的作用奠定基础。 此外，这些数据将被用作未来研究了解所涉及的机制的基础 CP感染在AD中的作用，最终目标是为这种毁灭性的疾病找到新的治疗方法。

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.