Transcriptional Control of Neuroinflammation in Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是最常见的老年性神经退行性疾病，影响约4400万人 全世界有550万人在美国大脑中有淀粉样斑块，这是糖尿病的病理标志之一。 AD由淀粉样β肽-40（Aβ-40）和淀粉样β肽-42（Aβ-42）的混合形式组成， 淀粉样蛋白前体蛋白通过顺序切割，并且对于AD的神经发病机制至关重要。尽管 主要的药物开发工作针对Aβ肽的切割和加工，几乎所有的实验药物 迄今为止，对AD进行的测试未能显示出显著的功效。迫切需要新的治疗策略 为AD提供新的预防和治疗意见，这是一个主要的未满足的医疗需求。Aβ 聚集体诱导氧化应激和炎症，导致小胶质细胞活化和神经变性， 大脑这一过程由促炎细胞因子如IL-17、IL-21、IL-22和IL-23提供动力， 通过CD 4 + T辅助17（Th 17）细胞，发现其在AD个体的外周血中升高 痴呆和轻度认知障碍（MCIAD）的正常老年对照组。值得注意的是，我们发现 小胶质细胞的主要转录因子Rorc和靶基因Il 18、Nos 2和Casp 4的表达， AD和MCIAD患者的脑中Rorc表达显著高于健康老年对照组， 女性比男性AD患者更显著。我们进一步发现Th 17细胞产生的IL-17和TNF α， 细胞诱导小鼠小胶质细胞中Rorc、Il 6、Il 18、Il 23和Tnfa的转录表达。由于IL-23可以 通过诱导致病性Th 17细胞发育，我们推测Th 17和小胶质细胞可能以一种积极的方式起作用， 反馈回路，促进炎症有助于AD发病机制。重要的是，我们的新布罗莫结构域 选择性靶向主要转录调节子BRD 4的抑制剂有效地抑制IL 17，IL 21， 小鼠Th 17细胞中的Il 22、Rorc和Il 6，以及小鼠原代小胶质细胞中的Il 6、Tnfa、Il 18、Il 23、Nos 2和Casp 4。 此外，MS 402阻断了实验性自身免疫性脑脊髓炎中Th 17细胞的过度产生。 小鼠，一种模拟人类神经炎性疾病的模型。我们的研究结果有力地表明， 我们的Th 17/小胶质细胞免疫调节剂作为一种新的治疗AD。由于我们的有利发现，在 本研究将（1）探讨Th 17和小胶质细胞在体外的转录调控机制， （2）开发和表征用于AD治疗的Th 17和小胶质细胞免疫调节剂;以及 (3)研究Th 17和小胶质细胞免疫调节剂在AD小鼠模型中体内治疗功效。

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.