Role of Class IIa HDACs HDAC4 and HDAC7 in Pathogenic Th17 Cell Development and Colitis

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PROJECT SUMMARY Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder of aging. The major pathological hallmark of AD in the brain amyloid plaques consists of amyloid β peptide-40 (Aβ40) and peptide-42 (Aβ42) that are produced from amyloid precursor proteins by sequential cleavage. However, nearly all experimental drugs targeting Aβ cleavage and processing tested for AD have failed to show significant efficacy. Alternative therapeutic options are being explored, as accumulating evidence has indicated that Aβ accumulation alone cannot explain much of the pathogenesis of AD, indicating the involvement of other pathological processes. Notably, neuroinflammation has emerged as a key player, as it is initiated by amyloid plaques, followed by activation of microglia and inflammatory CD4+ T-helper 17 (Th17) cells that eventually leads to neurodegeneration in the brain. This process is fueled by Th17-secreted inflammatory cytokines IL-17, IL-21, IL-22, IL-23, IFN-g and GM-CSF that are found to be elevated in AD patients. We recently discovered that Class IIa HDACs are essential for Th17 cell differentiation, but not Th1, Th2, and Treg subtypes that have different functions in immunity. Specifically, using genetic knockout mice, we found that Hdac4 activates gene transcription of Th17 cytokines IL-17A and IL-22 while Hdac7 represses gene transcription of Th17 negative regulators IL-2 and IL-10. Chemical disruption of HDAC4/7 by TMP269 attenuates inflammatory cytokine production by pathogenic Th17 cells and blocks Th17 over-development in experimental autoimmune encephalomyelitis (EAE) mice model and attenuates cognitive impairment in a mouse model of AD. Collectively, our results suggest that Class IIa HDACs are attractive new targets for neuroinflammation in AD.