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 β peptide-40 (Aβ-40) and amyloid β peptide-42 (Aβ-42) produced from amyloid precursor proteins by sequential cleavage, and are crucial for the neuro-pathogenesis of AD. Despite major drug development efforts targeting Aβ 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 opinions for AD that represents a major unmet medical need. Aβ 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 controls, 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.