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

项目摘要/摘要 阿尔茨海默病是一种在没有有效治疗的情况下使人衰弱的退行性疾病，在 流行率。开发有效的治疗方法受到阻碍，因为潜在的生物机制 驾驶疾病的发病机制目前仍知之甚少。淀粉样前体蛋白的异常裂解 产生聚集形式的神经毒性淀粉样β蛋白(Aβ)的APP一直是人们关注的焦点 调查了很多年。尽管APP基因突变引起的非常罕见的早发性家族性AD 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(&gt；95%)没有明确的遗传原因。许多风险相关基因(&gt；26)已经被发现， 但它们中的大多数在AD发病机制中的作用仍然知之甚少。小胶质细胞是先天存在的 介导对β蛋白的持续性神经炎性反应的免疫细胞 炎性细胞因子的产生、突触丢失和神经毒性。许多已识别的风险相关基因 似乎编码在小胶质细胞中表达的蛋白质，并参与吞噬和内溶酶体 贩运和蛋白降解，增加了小胶质细胞基本异常可能 导致Aβ处理不良和持续性神经炎，从而导致神经毒性和 阿尔茨海默病的神经退行性变。 血管紧张素转换酶(ACE)是一个研究很少的风险相关基因。以前的研究 我们发表的和强有力的初步数据表明，它在β从大脑中清除的过程中发挥着重要作用 在促进Aβ蛋白吞噬、其内酶体转运和蛋白降解方面 小胶质细胞。该项目被概括为三个具体目标：(1)研究ACE在小胶质细胞中的具体作用 在新的转基因小鼠和AD动物模型中，(2)检测ACE- 调节小胶质细胞的基因表达，并确定它们在吞噬、内毒素转运和 蛋白水解性降解和(3)血管紧张素转换酶在人诱导的小胶质细胞移植中的作用 在AD模型中研究它们在体内的反应。 数以百万计的人类患有阿尔茨海默病，但预防和治疗仍然非常糟糕。我们预料到 这些研究集中在AD风险相关基因血管紧张素转换酶及其在小胶质细胞β加工中的作用 识别增强Aβ蛋白处理的新的信号通路。此外，我们预计这些 研究可能阐明小胶质细胞的机制，可能被用来开发增强Aβ的治疗方法 蛋白稳定和减轻阿尔茨海默病患者大脑中的神经炎症。

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.