Mitigating neuroinflammation and enhancing neuronal integrity in Alzheimer's disease

减轻阿尔茨海默病的神经炎症并增强神经元完整性

• 批准号: 10707976
• 负责人: Jianjie Ma
• 金额: $ 68.82万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707976
• 关键词: Abeta synthesis; Address; Adverse effects; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Biochemical; Biology; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Cell membrane; Cerebrospinal Fluid; Chronic; Circulation; Clinical; Clinical Course of Disease; Clinical Treatment; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Deterioration; Disease Progression; Dose; Doxycycline; Experimental Designs; Family suidae; Free Radicals; Genes; Goals; Heart failure; Hippocampus; Human; Imaging Device; Impaired cognition; Impairment; Inflammation; Inflammatory; Injury; Innate Immune System; Interleukin-1 beta; Interleukin-6; Knock-in Mouse; Link; Lipopolysaccharides; Longevity; Maintenance; Memory impairment; Messenger RNA; Microglia; Moderate Exercise; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neuronal Injury; Neurons; Ohio; Organ; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiology; Pilot Projects; Play; Production; Protein Family; Proteins; Publications; Rattus; Recombinants; Research; Resistance; Rodent; Role; Safety; Senile Plaques; Signal Transduction; Skeletal Muscle; Stress; TRIM Gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Transgenic Mice; Translating; Traumatic Brain Injury; Universities; age related; age related neuroinflammation; aged; amyloid formation; chemokine; cognitive function; controlled cortical impact; cytokine; effective therapy; gene repair; innovation; insight; intravenous administration; live cell imaging; member; mouse model; nano-string; neural; neuroinflammation; neuron loss; neurophysiology; neuroprotection; neurotoxicity; novel; porcine model; preservation; prevent; promoter; repaired; response; slow potential; tissue repair

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?

项目摘要 阿尔茨海默氏病（AD）是与年龄依赖的神经退行性疾病有关 神经炎症以及大脑中淀粉样蛋白斑块和神经原纤维缠结的堆积。治疗性 利用神经炎症并恢复神经元完整性的方法可能是有效的 意味着减轻AD中神经退行性的进展。在这里，我们提供了支持 MG53是组织修复蛋白，可以通过保护神经元免受神经元的速度降低AD神经退行性的观念 压力诱导的损伤和与AD相关的神经炎症。 MG53是装饰的成员 蛋白质家族在细胞膜修复中起着至关重要的作用。而主要在骨骼中表达 肌肉，中等运动可以诱导MG53的分泌循环中，以引起其组织保护功能。 血液中MG53水平升高的转基因小鼠具有健康的寿命，并且对 压力引起的脑损伤。重组人MG53（RHMG53）蛋白，系统地给药，可以 渗透血脑屏障（BBB），以防止啮齿动物和猪中的创伤性脑损伤（TBI）。 MG53 还通过脑脊液中检测到的人类AD患者的BBB。此外 促进组织修复，MG53具有抗炎功能，可抑制与神经炎症相关 小鼠中具有TBI和LPS神经毒性。对AD小鼠的试点研究揭示了RHMG53的有益作用 通过控制小胶质细胞激活来增强神经元完整性并减少神经炎症。长期 该项目的术语目标是破译神经保护中MG53的生理学，并翻译基本 发现AD临床治疗的结果。我们已经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，临床广告研究和独特的动物模型 AD的目标是对MG53双重功能的机械理解来控制 在AD进展过程中，神经炎症和神经元完整性保存。设计实验 在本提案中，重点是解决以下三个基本问题：MG53如何 有助于维持与AD进展相关的神经完整性？什么是 小胶质细胞中MG53抗炎功能的机制？我们可以针对双重功能吗 MG53作为减轻与AD进展相关的神经退行性的一种手段？