R01AG072562

Transcriptional Control of Neuroinflammation in Alzheimer's Disease - Project Summary

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging, affecting about 44 million people worldwide, with 5.5 million in the U.S. Amyloid plaques in the brain, one of the pathological hallmarks of AD, consist of fibrillary forms of amyloid SS peptide-40 (ASS-40) and amyloid SS peptide-42 (ASS-42) produced from amyloid precursor proteins by sequential cleavage, and are crucial for the neuro-pathogenesis of AD. Despite major drug development efforts targeting ASS peptide cleavage and processing, nearly all experimental drugs tested for AD thus far have failed to show significant efficacy. New therapeutic strategies are urgently needed to offer new prevention and treatment options for AD, which represents a major unmet medical need.

ASS aggregates induce oxidative stress and inflammation, leading to microglia activation and neurodegeneration in the brain. This process is fueled by pro-inflammatory cytokines such as IL-17, IL-21, IL-22, and IL-23, secreted by CD4+ T-helper 17 (TH17) cells, which are found to be elevated in the peripheral blood of individuals with AD dementia and mild cognitive impairment (MCIAD) over normal aging control subjects. Notably, we discovered that expression of RORC, a major transcription factor of microglia, and target genes IL18, NOS2, and CASP4 are markedly increased in the brain of AD and MCIAD patients over healthy aging control subjects, and RORC up-regulation is more profound in female than male AD patients. We further found that IL-17 and TNFA, produced by TH17 cells, induce transcriptional expression of RORC, IL6, IL18, IL23, and TNFA in mouse microglia. Since IL-23 can induce pathogenic TH17 cell development, we postulate that TH17 and microglial cells likely act in a positive feedback loop to promote inflammation contributing to AD pathogenesis.

Importantly, our new bromodomain inhibitor that selectively targets major transcription regulator BRD4 effectively inhibits transcription of IL17, IL21, IL22, RORC, and IL6 in mouse TH17 cells, and IL6, TNFA, IL18, IL23, NOS2, and CASP4 in mouse primary microglia. Furthermore, MS402 blocks over-production of TH17 cells in experimental autoimmune encephalomyelitis in mice, a model mimicking the neuroinflammatory disorders in humans. Our results strongly suggest a promise of our TH17/microglia immunomodulators as a new treatment for AD.

Motivated by our favorable findings, in this study, we will:
(1) Investigate the mechanisms of transcriptional regulation of TH17 and microglial cells in AD pathogenesis;
(2) Develop and characterize TH17 and microglial immunomodulators for AD treatment; and
(3) Investigate in vivo therapeutic efficacy of TH17 and microglial immunomodulators in AD mouse models.

Icahn School Of Medicine At Mount Sinai

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]

New York, New York 100296504 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 397% from $844,476 to $4,195,970.