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: 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
• 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' 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; 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

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.

项目总结 阿尔茨海默病(AD)是最常见的神经退行性疾病，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，这是脑部疾病的病理特征之一 AD，由纤维形式的淀粉样蛋白β多肽-40(Aβ-40)和淀粉样蛋白β多肽-42(Aβ-42)组成 淀粉样前体蛋白通过顺序切割，在阿尔茨海默病的神经发病机制中起关键作用。尽管 主要药物开发工作针对Aβ多肽的裂解和加工，几乎所有实验药物 到目前为止，对AD的测试没有显示出显著的疗效。迫切需要新的治疗策略 为AD提供新的预防和治疗意见，这是一个主要的未得到满足的医疗需求。Aβ 聚集体诱导氧化应激和炎症，导致小胶质细胞激活和神经变性。 大脑。这一过程是由促炎细胞因子如IL-17、IL-21、IL-22和IL-23分泌的 通过CD4+T辅助17(Th17)细胞，发现AD患者外周血中的Th17细胞升高 痴呆和轻度认知障碍(MCIAD)高于正常年龄对照组受试者。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IL18、NOS2和Casp4的表达 AD和MCIAD患者脑内显著增加，超过健康老年对照组，RORC上调 在AD患者中，女性比男性更深刻。我们进一步发现，Th17产生的IL-17和TNFa 细胞，诱导小鼠小胶质细胞中RORC、IL6、IL18、IL23和TNFa的转录表达。由于IL-23可以 诱导致病Th17细胞发育，我们推测Th17和小胶质细胞可能在 反馈环促进炎症参与AD的发病机制。重要的是，我们的新溴域 选择性靶向主要转录调控因子BRD4的抑制剂有效地抑制IL17，IL21， 小鼠Th17细胞表达IL22、RORC和IL6，小鼠原代小胶质细胞表达IL6、TNFa、IL18、IL23、NOS2和Casp4。 此外，MS402可阻断实验性自身免疫性脑脊髓炎模型中Th17细胞的过度产生。 老鼠，一种模拟人类神经炎性疾病的模型。我们的结果有力地表明了一种前景 我们的Th17/小胶质细胞免疫调节剂作为治疗AD的新疗法。在我们有利的调查结果的激励下，在 在本研究中，我们将(1)探讨Th17和小胶质细胞的转录调控机制。 AD的发病机制；(2)开发和鉴定治疗AD的Th17和小胶质细胞免疫调节剂；以及 (3)观察Th17和小胶质细胞免疫调节剂对AD模型小鼠的体内治疗效果。