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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病。主要病理 脑淀粉样斑块中AD的标志物由淀粉样β肽-40（Aβ40）和肽-42（Aβ42）组成， 由淀粉样前体蛋白通过连续切割产生。然而，几乎所有的实验药物 针对AD测试的靶向Aβ切割和加工未能显示出显著的功效。替代 目前正在探索治疗方案，因为越来越多的证据表明，Aβ积聚本身 不能解释AD的发病机制，表明其他病理过程的参与。 值得注意的是，神经炎症已经成为一个关键因素，因为它是由淀粉样蛋白斑块引发的，然后是 小胶质细胞和炎性CD 4 + T辅助17（Th 17）细胞的活化，最终导致 大脑的神经退化该过程由Th 17分泌的炎性细胞因子IL-17，IL-21， IL-22、IL-23、IFN-g和GM-CSF在AD患者中升高。我们最近发现 IIa类HDAC是Th 17细胞分化所必需的，但不是Th 1、Th 2和Treg亚型， 不同的免疫功能。具体来说，使用基因敲除小鼠，我们发现Hdac 4激活基因 Th 17细胞因子IL-17 A和IL-22的转录，而Hdac 7抑制Th 17阴性细胞因子的基因转录。 调节因子IL-2和IL-10。TMP 269对HDAC 4/7的化学破坏减弱了炎性细胞因子 通过致病性Th 17细胞的产生并阻断实验性自身免疫中Th 17的过度发育 在一些实施方案中，本发明提供了一种治疗脑脊髓炎（EAE）小鼠模型的方法，并减轻AD小鼠模型中的认知损害。 总的来说，我们的结果表明，IIa类HDAC是AD神经炎症的有吸引力的新靶点。

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.