Transcriptional Control of Neuroinflammation in Alzheimer's Disease

阿尔茨海默病神经炎症的转录控制

基本信息

批准号：
10213328
负责人：
Dongming Cai
金额：
$ 84.45万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10213328
关键词：
Address Affect Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease test Alzheimer&apos s disease therapy Alzheimer&apos s neuropathogenesis Amyloid beta-Protein Amyloid beta-Protein Precursor Apolipoprotein E Autopsy Blood - brain barrier anatomy Brain Bromodomain CD4 Positive T Lymphocytes Cells Chemicals Clinical Trials Cognitive deficits Cultured Cells Dementia Development Disease Drug Kinetics Etiology Experimental Autoimmune Encephalomyelitis Feedback Female Genetic Transcription Genotype Human IL18 gene Immunomodulators Impairment Individual Inflammation Inflammatory Interleukin-17 Interleukin-6 Knock-in Mouse Lead Mediating Medical Microglia Modeling Molecular Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Oxidative Stress Pathogenesis Pathogenicity Pathologic Patients Peptides Peripheral Pharmaceutical Chemistry Pharmacology Phenotype Prevention Process Production Proteins Regulation Research Research Priority Role Senile Plaques Structure Therapeutic To specify Transcriptional Regulation Treatment Efficacy Up-Regulation Work apolipoprotein E-4 base brain tissue cytokine drug development drug testing healthy aging immunomodulatory therapies immunoregulation in vivo induced pluripotent stem cell inhibitor/antagonist interest interleukin-22 interleukin-23 male mild cognitive impairment mouse model neuroinflammation normal aging novel therapeutic intervention peripheral blood sex transcription factor

项目摘要

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.

项目概要阿尔茨海默病 (AD) 是最常见的衰老神经退行性疾病，影响约 4400 万人在美国，全世界有 550 万人的大脑中存在淀粉样蛋白斑块，这是淀粉样蛋白的病理标志之一 AD，由纤维形式的 β 淀粉样肽 40 (Aβ-40) 和 β 淀粉样肽 42 (Aβ-42) 产生，淀粉样蛋白前体蛋白通过连续裂解，并且对于 AD 的神经发病机制至关重要。主要药物开发工作针对 Aβ 肽裂解和加工，几乎所有实验药物迄今为止，针对 AD 的测试尚未显示出显着的疗效，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 Aβ 未满足的主要医疗需求。聚集体诱导氧化应激和炎症，导致小胶质细胞激活和神经退行性变该过程由大脑分泌的促炎细胞因子（例如 IL-17、IL-21、IL-22 和 IL-23）推动。由 CD4+ T 辅助细胞 17 (Th17) 细胞产生，这些细胞在 AD 患者的外周血中含量升高值得注意的是，我们发现正常衰老对照受试者的痴呆和轻度认知障碍（MCIAD）。 Rorc（小胶质细胞的主要转录因子）和靶基因 Il18、Nos2 和 Casp4 的表达与健康老龄对照组相比，AD 和 MCIAD 患者的大脑中 Rorc 上调显着增加我们进一步发现 Th17 产生的 IL-17 和 TNFa 在女性 AD 患者中的影响更为深远。 IL-23 可以诱导小鼠小胶质细胞中 Rorc、Il6、Il18、Il23 和 Tnfa 的转录表达。诱导致病性 Th17 细胞发育，我们假设 Th17 和小胶质细胞可能以积极的方式发挥作用重要的是，我们的新溴结构域促进了炎症的反馈循环。选择性靶向主要转录调节因子 BRD4 的抑制剂，有效抑制 Il17、Il21、小鼠 Th17 细胞中的 Il22、Rorc 和 Il6，以及小鼠原代小胶质细胞中的 Il6、Tnfa、Il18、Il23、Nos2 和 Casp4。此外，MS402 还可阻止实验性自身免疫性脑脊髓炎中 Th17 细胞的过度产生。小鼠，一种模仿人类神经炎症性疾病的模型，我们的结果强烈表明了这一前景。受我们有利的发现的推动，我们的 Th17/小胶质细胞免疫调节剂作为 AD 的新治疗方法。在本研究中，我们将 (1) 研究 Th17 和小胶质细胞的转录调控机制 AD 发病机制；(2) 开发和表征用于 AD 治疗的 Th17 和小胶质细胞免疫调节剂； (3)研究Th17和小胶质细胞免疫调节剂在AD小鼠模型中的体内治疗效果。