Modulating microglial function to restore A-beta proteostasis in Alzheimer's Disease

调节小胶质细胞功能以恢复阿尔茨海默病中的 A-β 蛋白质稳态

• 批准号: 10301741
• 负责人: WARREN G TOURTELLOTTE
• 金额: $ 189.48万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301741
• 关键词: ACE2; Abeta clearance; Address; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid; Amyloid Protein AA; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Automobile Driving; Autophagocytosis; Biological; Brain; Brain Diseases; Bypass; Cell physiology; Cells; Cessation of life; Chronic; Cleaved cell; Data; Degenerative Disorder; Dementia; Deposition; Disease; Doxycycline; Early Onset Familial Alzheimer' s Disease; Engraftment; Gene Abnormality; Gene Expression; Genes; Genetic; Homeostasis; Human; Immune; Impairment; In Vitro; Inflammatory; Inherited; Investigation; Lead; Learning; Life; Mediating; Mediator of activation protein; Memory impairment; Methods; Microglia; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Pathogenesis; Patients; Peptidyl-Dipeptidase A; Phagocytosis; Prevalence; Prevention; Production; Proteins; Publishing; Risk; Role; Signal Pathway; Synapses; Testing; Transgenic Mice; autosomal dominant mutation; cognitive function; cytokine; design; disease-causing mutation; effective therapy; engineered stem cells; experimental study; familial Alzheimer disease; human old age (65+); immune function; in vivo; induced pluripotent stem cell; mouse model; neuroinflammation; neuron loss; neurotoxic; neurotoxicity; novel; novel therapeutics; overexpression; presenilin-1; presenilin-2; protein degradation; proteostasis; response; trafficking; trend

PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease is a debilitating degenerative disease without effective treatment that is increasing in prevalence. Developing effective therapies has been impeded because the underlying biological mechanisms driving disease pathogenesis are still poorly understood. Abnormal cleavage of amyloid precursor protein (APP) that generates aggregating forms of neurotoxic amyloid-beta (Aβ) protein has been a focus of investigation for many years. Although very rare forms of early onset familial AD caused by mutations in APP or processing-associated proteins PSEN1 and PSEN2 substantiate a role for Aβ in the pathogenesis of AD, most cases (>95%) have no definitive genetic cause. Many risk-associated genes (>26) have been identified, but the role of most of them in AD pathogenesis remains very poorly understood. Microglia are resident innate immune cells that mediate persistent neuroinflammatory responses to Aβ protein characterized by increased inflammatory cytokine production, synapse loss and neurotoxicity. Many of the identified risk-associated genes appear to encode proteins that are expressed in microglia and involved in phagocytosis and endolysosomal trafficking and proteolytic degradation, raising the possibility that fundamental abnormalities in microglia may contribute to poor Aβ processing and persistent neuroinflammation that leads to neurotoxicity and neurodegeneration in AD. Angiotensin Converting Enzyme (ACE) is a very poorly studied risk-associated gene. Previous studies published by us and strong preliminary data indicate that it has a significant role in Aβ clearance from the brain and in enhancing Aβ protein phagocytosis, its endolysosomal trafficking and proteolytic degradation in microglia. The project is outlined in three specific aims to: (1) examine the role of ACE specifically in microglia in novel transgenic mice and in an animal model of AD, (2) examine the molecular mechanisms of ACE- regulated gene expression in microglia and determine their role in phagocytosis, endolysosomal trafficking and proteolytic degradation and (3) characterize the function of ACE in human induced microglia engrafted into mice brains to study their response in vivo in a model of AD. Millions of humans are afflicted with AD, yet prevention and treatment remain very poor. We anticipate that these studies focused on the AD risk-associated gene ACE and its role in Aβ processing in microglia will identify novel signaling pathways that enhance Aβ protein processing. Moreover, we anticipate that these studies may elucidate mechanisms in microglia that may be exploited to develop treatments to enhance Aβ proteostasis and mitigate neuroinflammation in the brain in AD.

项目概要/摘要 阿尔茨海默病是一种令人衰弱的退行性疾病，没有有效的治疗方法，这种疾病的发病率正在不断增加 由于潜在的生物学机制，开发有效的治疗方法受到阻碍。 淀粉样前体蛋白的异常裂解对驱动疾病的发病机制仍知之甚少。 （APP）产生聚集形式的神经毒性淀粉样β（Aβ）蛋白一直是人们关注的焦点 尽管由 APP 突变引起的早发型家族性 AD 的情况非常罕见。 或加工相关蛋白 PSEN1 和 PSEN2 证实了 Aβ 在 AD 发病机制中的作用， 大多数病例（>95%）没有明确的遗传原因，许多风险相关基因（>26）已被识别。 但其中大多数在 AD 发病机制中的作用仍知之甚少，小胶质细胞是固有的。 免疫细胞介导对 Aβ 蛋白的持续神经炎症反应，其特征是增加 炎症细胞因子的产生、突触损失和神经毒性许多已确定的风险相关基因。 似乎编码在小胶质细胞中表达并参与吞噬作用和内溶酶体的蛋白质 贩运和蛋白水解降解，增加了小胶质细胞基本异常可能的可能性 导致 Aβ 加工不良和持续的神经炎症，从而导致神经毒性和 AD 中的神经变性。 血管紧张素转换酶（ACE）是一种研究很少的风险相关基因。 我们发表的和强有力的初步数据表明它在大脑中 Aβ 清除中具有重要作用 在 A 中增强β蛋白的吞噬作用，其内溶酶体运输和蛋白水解降解 该项目概述了三个具体目标：(1) 研究 ACE 在小胶质细胞中的具体作用。 在新型转基因小鼠和 AD 动物模型中，(2) 检查 ACE- 的分子机制 调节小胶质细胞中的基因表达并确定它们在吞噬作用、内溶酶体运输和 蛋白水解降解和（3）表征 ACE 在植入人类诱导小胶质细胞中的功能 小鼠大脑在 AD 模型中研究其体内反应。 数百万人患有 AD，但我们预计预防和治疗仍然很差。 这些研究重点关注 AD 风险相关基因 ACE 及其在小胶质细胞 Aβ 加工中的作用。 确定增强 Aβ 蛋白加工的新信号通路。 研究可能会阐明小胶质细胞的机制，可用于开发增强 Aβ 的治疗方法 AD 患者大脑中的蛋白质稳态并减轻神经炎症。