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 阿尔茨海默病(AD)是一种年龄相关的神经退行性疾病，与慢性 神经炎症和大脑中淀粉样斑块和神经原纤维缠结的积聚。一种治疗方法 治疗神经炎症和恢复神经元完整性的方法可能是一种潜在的有效方法 缓解阿尔茨海默病神经退行性变的手段。在这里，我们提供了新的发现来支持 认为MG53是一种组织修复蛋白，可以通过保护神经元免受 应激诱导的损伤和减轻与AD相关的神经炎症。MG53是TRIM的成员之一 在细胞膜修复中起重要作用的蛋白质家族。虽然主要在骨骼中表达 肌肉方面，适度运动可诱导MG53分泌进入循环，从而发挥其组织保护作用。 血液中MG53水平升高的转基因小鼠活得很健康，并对 应激导致的脑损伤。全身给药的重组人MG53(RhMG53)蛋白可以 渗透血脑屏障(BBB)以保护啮齿动物和猪的创伤性脑损伤(TBI)。MG53 也通过人类AD患者的血脑屏障，因为它是在脑脊液中检测到的。除了……之外 促进组织修复，MG53具有抗炎功能，可抑制相关的神经炎症 对小鼠有脑损伤和脂多糖神经毒性作用。对AD小鼠的初步研究显示，重组人MG53对 通过控制小胶质细胞的激活，增强神经元的完整性，减少神经炎症。长的- 本项目的学期目标是破译MG53在神经保护方面的生理学并翻译基本的 阿尔茨海默病的临床治疗结果。我们组建了一支在以下领域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、临床阿尔茨海默病研究和独特的动物模型 目的是对MG53的S在控制中的双重作用达成机械性的理解 在阿尔茨海默病进展过程中神经炎症和神经元完整性的保护。设计的实验 在这项提案中，重点解决了以下三个基本问题：MG53如何 有助于维持与阿尔茨海默病进展相关的神经完整性？什么是 MG53的S在小胶质细胞中的抗炎作用机制？我们可以针对双重功能吗 MG53作为减缓与AD进展相关的神经退行性变的手段？