Endocannabinoids in Neurodegenerative Diseases

神经退行性疾病中的内源性大麻素

• 批准号: 8370186
• 负责人: CHU CHEN
• 金额: $ 31.5万
• 依托单位: LSU HEALTH SCIENCES 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370186
• 关键词: 2-arachidonylglycerol; 3' Untranslated Regions; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Binding Sites; Biological Assay; Brain; CNR1 gene; CNR2 gene; Cessation of life; Cleaved cell; Crossbreeding; Dementia; Deposition; Deterioration; Development; Disease Progression; Endocannabinoids; Enzymes; Epigenetic Process; Fatty Acids; Functional disorder; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Knockout Mice; Lead; Mediating; Memory; Messenger RNA; MicroRNAs; Molecular; Monoacylglycerol Lipases; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathogenesis; Pharmaceutical Preparations; Play; Porifera; Prevention; Production; Property; Proteins; Regulation; Research; Role; Screening procedure; Senile Plaques; Signal Transduction; Site; Staging; Synapses; Testing; Transgenic Animals; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; beta-site APP cleaving enzyme 1; cognitive function; improved; inhibitor/antagonist; mind control; neuroinflammation; neuropathology; novel; prevent; protein expression; synaptic function

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia among older people. AD is characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread degenerated neurons and neuronal death. Currently, there are no effective medications to prevent and treat AD and halt the disease progression. This is largely due to our limited understanding of the mechanisms involved in the development and neuropathology of AD. Endocannabinoids are naturally occurring fatty acids displaying anti-inflammatory and neuroprotective properties. Recently we demonstrated that exogenous and endogenous 2-arachidonoylglycerol (2-AG) protects hippocampal neurons in culture against beta-amyloid- induced neurodegeneration and neuroinflammation. In particular, our ongoing research revealed that strengthening 2-AG signaling by inhibition of monoacylglycerol lipase (MAGL), the enzyme metabolizing 2-AG, robustly reduced protein expression of beta-site APP cleaving enzyme 1 (BACE1), the key enzyme for A-beta synthesis, and decreased deposition of A-beta plaques, neuroinflammation and neurodegeneration, and improved synaptic and cognitive function in an animal model of AD. This means that 2-AG likely plays an important role in counteracting pathogenesis and neuropathology of AD. Previous studies demonstrated that expression of BACE1 at protein levels, but not at mRNA levels, is elevated, both in AD human and animals, suggesting that expression of BACE1 is regulated by an epigenetic mechanism at post-transcriptional levels. Our preliminary studies revealed that expression of the noncoding microRNAs targeting BACE1, was significantly down-regulated both in the brains of AD humans and animals, but the expression was returned to the normal control levels when brain 2-AG levels were elevated in APP transgenic AD animals. Thus, we hypothesize that the actions of brain 2-AG signaling in preventing and reducing pathogenesis and neuropathology of AD are through CB1 receptor-dependent regulation of the expression of the specific miRNAs that repress BACE1, resulting in decreases in A-beta production and accumulation, neuroinflammation and degeneration and improvements in synaptic and cognitive function in AD animals. The proposed project will not only provide molecular mechanisms of strengthening 2-AG signaling in preventing or decreasing pathogenesis and neuropathology of AD, but also will open a new area for the development and discovery of novel drugs aimed at preventing and treating AD, or slowing AD progression. PUBLIC HEALTH RELEVANCE: The proposed application will tackle a novel and intriguing topic that 2-AG signaling is crucial in maintaining homeostasis of normal brain function and its beneficial effects are likely through CB1 receptor-dependent regulation of miRNAs that target the enzyme synthesizing beta-amyloid. The results generated from this application will not only provide molecular mechanisms of strengthening 2-AG signaling in preventing or decreasing pathogenesis and neuropathology of AD, but also will open a new area for the development and discovery of novel drugs aimed at preventing and treating AD, or slowing AD progression.

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆症最常见的原因。AD的特征在于淀粉样蛋白斑块和神经元缠结的积累和沉积、神经炎症、突触功能障碍、认知功能的进行性恶化以及与广泛变性的神经元和神经元死亡相关的记忆丧失。目前，没有有效的药物来预防和治疗AD并阻止疾病进展。这在很大程度上是由于我们对AD的发展和神经病理学机制的了解有限。内源性大麻素是天然存在的脂肪酸，具有抗炎和神经保护作用。最近，我们证明，外源性和内源性2-花生四烯酸甘油（2-AG）保护海马神经元在培养β-淀粉样蛋白诱导的神经变性和神经炎症。特别是，我们正在进行的研究表明，通过抑制单酰基甘油脂肪酶（MAGL）（代谢2-AG的酶）来加强2-AG信号传导，可显著降低β位点APP裂解酶1（BACE 1）（A-β合成的关键酶）的蛋白表达，减少A-β斑块的沉积，神经炎症和神经变性，并改善AD动物模型中的突触和认知功能。这意味着2-AG可能在对抗AD的发病机制和神经病理学中起重要作用。先前的研究表明，在AD人和动物中，BACE 1在蛋白质水平而不是在mRNA水平上的表达升高，表明BACE 1的表达在转录后水平上受到表观遗传机制的调节。我们的初步研究显示，在AD人和动物的脑中，靶向BACE 1的非编码microRNA的表达显著下调，但当APP转基因AD动物的脑2-AG水平升高时，表达恢复到正常对照水平。因此，我们假设脑2-AG信号传导在预防和减少AD的发病机制和神经病理学中的作用是通过CB 1受体依赖性调节抑制BACE 1的特异性miRNA的表达，导致AD动物中A-β产生和积累、神经炎症和变性的减少以及突触和认知功能的改善。该项目不仅将提供加强2-AG信号传导在预防或减轻AD发病机制和神经病理学方面的分子机制，而且将为开发和发现旨在预防和治疗AD或减缓AD进展的新药开辟新领域。 公共卫生关系：该申请将解决一个新颖而有趣的主题，即2-AG信号传导在维持正常脑功能的稳态中至关重要，其有益作用可能是通过CB 1受体依赖性调节靶向合成β-淀粉样蛋白的酶的miRNA。该应用产生的结果不仅将提供加强2-AG信号传导以预防或减少AD的发病机制和神经病理学的分子机制，而且将为旨在预防和治疗AD或减缓AD进展的新药的开发和发现开辟新的领域。