The role of Chlamydia pneumoniae infection in Alzheimer's Disease

点击翻译按钮获取中文摘要

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.