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 ß (Aß) 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-1ß 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/PS1¿E9
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.