Mitigating neuroinflammation and enhancing neuronal integrity in Alzheimer's disease

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种与慢性阿尔茨海默病相关的年龄依赖性神经退行性疾病。 神经炎症和淀粉样蛋白斑块和脑中神经纤维缠结的积聚。治疗 利用神经炎症和恢复神经元完整性的方法可能是一种有效的 意味着缓解AD中神经变性的进展。在这里，我们提供了新的发现，支持 MG 53是一种组织修复蛋白，它可以通过保护神经元免受AD的损伤来减缓AD的神经变性。 应激诱导的损伤和减轻与AD相关的神经炎症。MG 53是TRIM的成员 在细胞膜修复中起重要作用的蛋白质家族。虽然主要在骨骼肌中表达， 肌肉，适度的运动可以诱导MG 53分泌到循环中，以引起其组织保护功能。 血液中MG 53水平增加的转基因小鼠寿命健康，并且对 压力导致的脑损伤全身施用的重组人MG 53（rhMG 53）蛋白可以 渗透血脑屏障（BBB），以防止啮齿动物和猪的创伤性脑损伤（TBI）。MG53 也通过人AD患者的BBB，因为它在脑脊液中被检测到。除了 促进组织修复，MG 53具有抗炎功能，抑制与神经炎症相关的神经炎症， 与TBI和LPS神经毒性的关系。AD小鼠的初步研究揭示了rhMG 53对AD小鼠的有益作用。 增强神经元的完整性，并通过控制小胶质细胞的活化来减少神经炎症。很长的- 该项目的长期目标是破译MG 53在神经保护中的生理学，并将其基本功能转化为 用于AD的临床治疗。我们组建了一个具有互补专业知识的团队， 神经生理学、小胶质细胞生物学、创新的活细胞成像、临床AD研究和独特的动物模型 目的是对MG 53在控制AD中的双重功能有一个机械的理解。 在AD进展过程中，神经炎症和神经元完整性的保护。设计的实验 在本提案中，重点关注以下三个基本问题：MG 53如何 有助于维持与AD进展相关的神经完整性？有哪些 MG 53在小胶质细胞中抗炎作用的机制？我们能把双重功能 MG 53作为缓解与AD进展相关的神经变性的手段？

Project Summary Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder associated with chronic neuroinflammation and the build-up of amyloid plaques and neurofibrillary tangles in the brain. A therapeutic approach that harnesses neuroinflammation and restores neuronal integrity can potentially be an effective means to alleviate the progression of neurodegeneration in AD. Here we provide novel findings supporting the notion that MG53, a tissue repair protein, can potentially slow AD neurodegeneration by protecting neurons from stress-induced injuries and mitigating neuroinflammation associated with AD. MG53 is a member of the TRIM protein family that plays an essential role in cell membrane repair. While predominantly expressed in skeletal muscle, moderate exercise can induce secretion of MG53 into circulation to elicit its tissue protective function. Transgenic mice with increased levels of MG53 in the bloodstream live a healthy lifespan and are resistant to stress-induced brain injury. Recombinant human MG53 (rhMG53) protein, administered systemically, can permeate the blood-brain barrier (BBB) to protect against traumatic brain injuries (TBI) in rodents and pigs. MG53 also passes through the BBB of human AD patients as it is detected in cerebrospinal fluid. In addition to facilitating tissue repair, MG53 has an anti-inflammation function that dampens neuroinflammation associated with TBI and LPS-neurotoxicity in mice. Pilot studies with AD mice reveal beneficial effects of rhMG53 to enhance neuronal integrity and reduce neuroinflammation through control of microglia activation. The long- term goal of this project is to decipher the physiology of MG53 in neuroprotection and to translate the basic findings into a clinical treatment for AD. We have assembled a team with complementary expertise in neurophysiology, microglia biology, innovative live-cell imaging, clinical AD research and unique animal models of AD, with the goal to arrive at a mechanistic understanding of MG53's dual function in control of neuroinflammation and in preservation of neuronal integrity during AD progression. The experiments designed in this proposal are focused on addressing the following three fundamental questions: How does MG53 contribute to the maintenance of neural integrity associated with the progression of AD? What are the mechanisms that underlie MG53's anti-inflammation function in the microglia? Can we target the dual function of MG53 as a means for alleviation of neurodegeneration associated with the progression of AD?