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?

项目概要 阿尔茨海默病 (AD) 是一种与年龄相关的慢性神经退行性疾病 神经炎症以及大脑中淀粉样斑块和神经原纤维缠结的积聚。一种治疗性的 利用神经炎症并恢复神经元完整性的方法可能是一种有效的方法 旨在缓解 AD 神经变性的进展。在这里，我们提供了支持以下观点的新发现： MG53 是一种组织修复蛋白，可以通过保护神经元免受 压力引起的损伤并减轻与 AD 相关的神经炎症。 MG53是TRIM成员 在细胞膜修复中发挥重要作用的蛋白质家族。虽然主要表达在骨骼中 肌肉中，适度的运动可以诱导 MG53 分泌到循环中，从而发挥其组织保护功能。 血液中 MG53 水平增加的转基因小鼠拥有健康的寿命并且对 压力引起的脑损伤。全身施用重组人 MG53 (rhMG53) 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 正如在脑脊液中检测到的那样，它也可以通过人类 AD 患者的血脑屏障。此外 MG53 具有抗炎功能，可促进组织修复，抑制与神经炎症相关的炎症 小鼠的 TBI 和 LPS 神经毒性。 AD 小鼠的初步研究揭示了 rhMG53 对 AD 小鼠的有益作用 通过控制小胶质细胞激活增强神经元完整性并减少神经炎症。长- 该项目的长期目标是破译 MG53 在神经保护方面的生理学原理，并转化其基本原理 AD 临床治疗的发现。我们组建了一支具有互补专业知识的团队 神经生理学、小胶质细胞生物学、创新活细胞成像、临床 AD 研究和独特的动物模型 AD 的研究，目标是对 MG53 控制的双重功能有一个机械理解 AD 进展过程中的神经炎症和神经元完整性的保护。所设计的实验 该提案重点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？有哪些 MG53 在小胶质细胞中的抗炎功能的机制是什么？我们可以针对双重功能吗 MG53 作为缓解与 AD 进展相关的神经变性的一种手段？