Transcriptional Control of Neuroinflammation in Alzheimer's Disease

阿尔茨海默病神经炎症的转录控制

• 批准号: 10574605
• 负责人: Dongming Cai
• 金额: $ 84.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10574605
• 关键词: Address; Affect; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease test; Alzheimer' s disease therapy; Alzheimer' s neuropathogenesis; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Autopsy; Blood - brain barrier anatomy; Brain; Bromodomain; CD4 Positive T Lymphocytes; Cells; Central Nervous System; Chemicals; Clinical Trials; Cognitive deficits; Dementia; Development; Disease; Drug Kinetics; Etiology; Experimental Autoimmune Encephalomyelitis; Feedback; Female; Genetic Transcription; Genotype; Human; IL17 gene; IL18 gene; Immunomodulators; Impairment; Individual; Inflammation; Inflammatory; Interleukin-6; Knock-in Mouse; Lead; Mediating; Medical; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Oxidative Stress Induction; Pathogenesis; Pathogenicity; Pathologic; Peptides; Peripheral; Persons; Pharmaceutical Chemistry; Phenotype; Prevention; Process; Production; Proteins; Regulation; Research; Research Priority; Role; Senile Plaques; Specific qualifier value; Structure; Therapeutic; Transcriptional Regulation; Treatment Efficacy; Up-Regulation; Work; abeta accumulation; apolipoprotein E-4; blood-brain barrier crossing; brain tissue; cytokine; drug development; drug testing; healthy aging; immunomodulatory therapies; immunoregulation; in vivo; induced pluripotent stem cell; inhibitor; interest; interleukin-21; interleukin-22; interleukin-23; male; mild cognitive impairment; mouse model; neuroinflammation; normal aging; novel therapeutic intervention; peripheral blood; pharmacologic; sex; transcription factor

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.

项目摘要 阿尔茨海默氏病（AD）是衰老的最普遍的神经退行性疾病，影响约4400万 在美国，全球占地550万个大脑的淀粉样蛋白斑块，这是病理学的标志之一 AD由淀粉样β肽-40（Aβ-40）和淀粉样β肽-42（Aβ-42）的原纤维形式组成 淀粉样蛋白前体蛋白通过顺序切割，对于AD的神经性致病作用至关重要。尽管 针对Aβ肽裂解和加工的主要药物开发工作，几乎所有实验药物 到目前为止，对AD的测试未能显示出明显的效率。迫切需要新的治疗策略 为AD提供新的预防和治疗意见，代表了主要未满足的医疗需求。 Aβ 聚集体诱导氧化应激和注射，从而导致小胶质细胞激活和神经退行性在 大脑。促炎细胞因子（例如IL-17，IL-21，IL-22和IL-23）促进了此过程 通过CD4+ T-Helper 17（Th17）细胞，发现在AD的个体的外周血中升高 正常衰老对照受试者的痴呆和轻度认知障碍（MCIAD）。值得注意的是，我们发现了 RORC的表达是小胶质细胞的主要转录因子，靶基因IL18，NOS2和CASP4的表达是 在健康的衰老对照方面，AD和MCIAD患者的大脑显着增加，RORC上调 女性比男性广告患者更深刻。我们进一步发现，IL-17和TNFA，由Th17生产 细胞，诱导小鼠小胶质细胞中RORC，IL6，IL18，IL23和TNFA的转录表达。因为IL-23可以 诱导致病性Th17细胞发育，我们假设Th17和小胶质细胞可能作用于正面 反馈回路促进炎症导致AD发病机理。重要的是，我们的新溴化域 选择性靶向主要转录器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阻止了实验性自身免疫性脑脊髓炎中Th17细胞过量生产 小鼠，一种模型，模仿了人类的神经炎性疾病。我们的结果强烈暗示了一个承诺 我们的Th17/小胶质细胞免疫调节剂作为AD的新方法。受我们有利的发现的动机， 这项研究，我们将（1）研究Th17和小胶质细胞转录调节的机理 AD发病机理； （2）开发和表征Th17和小胶质细胞免疫调节剂进行AD治疗；和 （3）研究AD小鼠模型中Th17和小胶质细胞免疫调节剂的体内治疗有效性。