PROJECT SUMMARY This administrative supplement application is submitted for the parent award (5R01AI124465- 05) in response to NIH funding opportunity (NOT-AG-20-008), entitled “Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease.” 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 are one of the pathological hallmarks of AD. The plaques mainly 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. Despite the major drug development efforts targeting amyloid β peptide cleavage and processing, nearly all experimental drugs tested for AD thus far have failed to show significant efficacy. Recent studies show that Aβ peptides form aggregates that induce oxidative stress and initiate the inflammatory process, leading to activation of microglial and neurodegeneration in the brain, which is fueled by proinflammatory cytokines secreted by CD4+ T-helper 17 (Th17) cells. These studies suggest a new therapeutic strategy of targeting neuroinflammatory Th17 cells in the AD pathogenesis to prevent and treat AD. Studies from us and others show that Th17 cell differentiation from naïve CD4+ T cells is tightly regulated in gene transcription by coordinated activities of major transcription and chromatin regulators including BET family protein BRD4. We recently developed a set of novel small-molecule compounds that selectively target BRD4 activity for transcriptional expression of Th17 signature cytokines including IL-17, IL-21, IL-22, and IL-23, and blocks over-development of Th17 cells in mice that mimic the conditions of neuroinflammatory disorders in humans. Motivated by our favorable findings, in this study, we propose to: (1) develop our CNS penetrant Th17 immunomodulators, and (2) characterize them in the AD mouse model as a new immunomodulation treatment for AD, which represents a major unmet medical need.