R01AG075998

The Role of Chlamydia Pneumoniae Infection in Alzheimer's Disease

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/PS1E9 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/PS1E9 (ADTG) mice.
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).
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 in CP infection's role in AD, with the ultimate goal leading to new therapeutic approaches for this devastating disease.

Cedars-Sinai Medical Center

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Los Angeles, California 900481804 United States

Single Zip Code

Infectious Etiology of Alzheimer's Disease (R01 Clinical Trial Optional) (RFA-AG-21-034)

Amendment Since initial award the total obligations have increased 398% from $662,840 to $3,300,943.