Endocannabinoids in neurodegenerative diseases

内源性大麻素在神经退行性疾病中的作用

• 批准号: 10590929
• 负责人: CHU CHEN
• 金额: $ 215.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590929
• 关键词: 2-arachidonylglycerol; Acceleration; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Diseases; Animal Model; Anti-Inflammatory Agents; Astrocytes; Attenuated; Brain; Complex; Dementia; Development; Disease Progression; Elderly; Endocannabinoids; Enzymes; Etiology; Funding; Genetic; Goals; Hippocampus; Impaired cognition; Impairment; Learning; MAGL inhibitor; Mediating; Memory; Metabolism; Molecular; Monoacylglycerol Lipases; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Pathologic Processes; Persons; Physiological Processes; Prevention; Property; Research; Resolution; Signal Transduction; Structure; Synapses; Tauopathies; Traumatic Brain Injury; United States; adeno-associated viral vector; cell type; cognitive function; effective therapy; efficacious treatment; functional plasticity; improved; lipid mediator; neuroinflammation; neuropathology; neuroprotection; novel therapeutics; overexpression; pharmacologic; prevent; protective effect; restraint; synaptic function; tau Proteins; therapeutic target

Summary Dementia affects millions of people in the United States. Alzheimer’s disease (AD) is one of the most common causes of dementia in elderly. However, there are no effective therapies currently available for preventing and treating AD or halting progression of the disease. Therefore, it is imperative to develop efficacious therapies for AD. Although the etiology of AD is multifactorial and complex, accumulated evidence suggests that neuroinflammation is a root cause of neurodegenerative diseases, including AD. Hence, resolving neuroinflammation is crucial for preventing development of AD or for modifying disease progression. Endocannabinoids are naturally occurring bioactive lipid mediators involved in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG), the most abundant endocannabinoid, displays profound anti-inflammatory and neuroprotective properties. Inhibition of 2-AG degradation by pharmacological inactivation of monoacylglycerol lipase (MAGL), the key enzyme that degrades 2-AG in the brain, has been shown to produce neuroprotective effects in AD, and thus MAGL has been proposed as a therapeutic target for AD. During the current funding period, we discovered that genetic inactivation of MAGL reduces neuropathology and averts synaptic and cognitive declines in an animal model of traumatic brain injury (TBI). Surprisingly, these neuroprotective effects result primarily from augmentation of 2-AG signaling in astrocytes, rather than in neurons, suggesting that the neuroprotective effects induced by inactivation of MAGL in TBI are through 2-AG-mediated cell type-specific resolution of neuroinflammation. In this competing renewal application, we propose to determine whether genetic inactivation of MAGL produces anti-inflammatory and neuroprotective effects in animal models of AD and whether the protective effects are also cell type-specific. To reach this goal, we will assess beta-amyloid (Aβ) and tau neuropathology, structural and functional plasticity of synapses, and cognitive function by cell type-specific inactivation of MAGL in animal models of AD and delineate the molecular mechanisms that contribute to the MAGL inactivation-produced neuroprotective effects in AD. The outcome of the proposed research will enable us to better development of efficacious therapies or to refine treatments for AD.

总结 痴呆症影响着美国数百万人。阿尔茨海默病（AD）是最常见的疾病之一， 老年痴呆症的病因然而，目前还没有有效的治疗方法可用于预防和 治疗AD或阻止疾病的进展。因此，必须开发有效的治疗方法， AD.虽然AD的病因是多因素的和复杂的，但积累的证据表明， 神经炎症是包括AD在内的神经变性疾病的根本原因。因此，解决 神经炎症对于预防AD的发展或对于改变疾病进展至关重要。 内源性大麻素是天然存在的生物活性脂质介质，参与多种生理和病理过程。 病理过程。2-花生四烯酸甘油（2-AG），最丰富的内源性大麻素，显示深刻的 抗炎和神经保护特性。通过药物灭活抑制2-AG降解 单酰基甘油脂肪酶（MAGL），在大脑中降解2-AG的关键酶，已被证明可以产生 MAGL在AD中具有神经保护作用，因此已经提出MAGL作为AD的治疗靶标。期间 在目前的资助期内，我们发现MAGL的遗传失活减少了神经病理学， 在创伤性脑损伤（TBI）动物模型中的突触和认知下降。令人惊讶的是，这些 神经保护作用主要是由于星形胶质细胞中2-AG信号的增强，而不是神经元中， 提示MAGL失活诱导的TBI神经保护作用是通过2-AG介导的， 神经炎症的细胞类型特异性消退。在此竞争性续期申请中，我们建议 确定MAGL的基因失活是否在神经系统中产生抗炎和神经保护作用。 AD的动物模型以及保护作用是否也是细胞类型特异性的。为了实现这一目标，我们将 评估β-淀粉样蛋白（Aβ）和tau神经病理学，突触的结构和功能可塑性，以及认知功能。 在AD动物模型中，通过MAGL的细胞类型特异性失活来发挥功能，并描述了 在AD中，MAGL失活产生神经保护作用的机制。的结果 拟议的研究将使我们能够更好地开发有效的治疗方法或改进治疗方法， AD.