Endocannabinoids in Neurodegenerative Diseases

神经退行性疾病中的内源性大麻素

基本信息

批准号：
9919000
负责人：
CHU CHEN
金额：
$ 38.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919000
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Animals Anti-Inflammatory Agents Astrocytes Attention Brain Brain Injuries CNR1 gene Clinical Closed head injuries Complex Dementia Deterioration Development Disease Progression Endocannabinoids Enzymes Epidemiology Etiology Functional disorder Funding Genetic Genetic study Impaired cognition Impairment Incidence Injury Knock-out Knockout Mice Knowledge Laboratory Animals Lead Learning MAGL inhibitor Mediating Memory Metabolism Monoacylglycerol Lipases Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neurons Peroxisome Proliferator-Activated Receptors Pharmacology Pharmacology Study Play Production Property Recovery Risk Factors Role Signal Pathway Synapses Synaptic plasticity TDP-43 aggregation Testing Traumatic Brain Injury cell type cognitive function conditional knockout effective therapy improved lipid mediator mouse model neurodegenerative dementia neuroinflammation neuropathology new therapeutic target novel therapeutic intervention prevent protein TDP-43 synaptic function tau-1 therapeutic target vector

2-arachidonylglycerol 2-arachidonylglycerol signaling Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Animals Anti-Inflammatory Agents Astrocytes Attention Brain Brain Injuries CNR1 gene Clinical Closed head injuries Complex Dementia Deterioration Development Disease Progression Endocannabinoids Enzymes Epidemiology Etiology Functional disorder Funding Genetic Genetic study Impaired cognition Impairment Incidence Injury Knock-out Knockout Mice Knowledge Laboratory Animals Lead Learning MAGL inhibitor Mediating Memory Metabolism Monoacylglycerol Lipases Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neurons Peroxisome Proliferator-Activated Receptors Pharmacology Pharmacology Study Play Production Property Recovery Risk Factors Role Signal Pathway Synapses Synaptic plasticity TDP-43 aggregation Testing Traumatic Brain Injury cell type cognitive function conditional knockout effective therapy improved lipid mediator mouse model neurodegenerative dementia neuroinflammation neuropathology new therapeutic target novel therapeutic intervention prevent protein TDP-43 synaptic function tau-1 therapeutic target vector

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项目摘要

Summary While the etiology of Alzheimer's disease (AD) is multifactorial and complex, results from epidemiological, clinical, and laboratory animal studies implicate traumatic brain injury (TBI) as an important risk factor for AD and dementia. However, the mechanisms by which TBI increases the risk of AD are largely unknown. In particular, there are no effective therapies to prevent or treat TBI-caused AD neuropathology and dementia. Accumulating evidence suggests that neuroinflammation following the primary injury plays a critical factor in secondary brain damage and subsequent neuropathological changes. Therefore, resolving neuroinflammation will significantly reduce secondary brain damage and eventually prevent or reduce the incidence of TBI- induced AD-like neurodegenerative disease. Endogenous cannabinoids display anti-inflammatory and neuroprotective properties. During the current period of funding, we provided evidence that monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is likely a new therapeutic target for AD. Pharmacological inactivation of MAGL reduces neuropathology and improves synaptic plasticity and memory formation in animal models of both TBI and AD. However, we do not know whether genetic disruption of MAGL will yield beneficial effects similar to those following pharmacological inhibition of MAGL in TBI. In addition, there is a gap in our knowledge about the signaling pathways that mediate anti-inflammatory and neuroprotective effects produced by MAGL inhibition in TBI. In this competing renewal application, we propose to test our hypothesis that alleviation of TBI-induced AD-like neuropathological changes by pharmacological or genetic disruption of MAGL is primarily mediated by enhancement of 2-AG signaling in astrocytes, which, in turn curbs neuroinflammation. Thus, the primary objective of the studies proposed in this application will use our established mouse model of repetitive mild closed head injury to demonstrate that inhibition of 2-AG metabolism by pharmacological inhibition or genetic disruption of MAGL ameliorates AD-like neuropathology, improves recovery of synaptic and cognitive functions, and halts disease progression and delineate the signaling pathways that mediate the beneficial effects produced by MAGL inhibition. The results from this project may ultimately lead to development of a novel therapeutic intervention for TBI-induced AD-like neurodegenerative disease.

概括尽管阿尔茨海默氏病（AD）的病因是多因素和复杂的，但流行病学的结果是临床和实验室动物研究暗示创伤性脑损伤（TBI）是AD的重要危险因素和痴呆症。但是，TBI增加AD风险的机制在很大程度上未知。在特别是没有有效的疗法来预防或治疗TBI引起的AD神经病理学和痴呆症。积累的证据表明，主要伤害后的神经炎症是继发性脑损伤和随后的神经病理学变化。因此，解决神经炎症将显着减少脑损伤，并最终预防或减少TBI的发生率诱导广告样神经退行性疾病。内源性大麻素显示抗炎和神经保护特性。在当前的资金期间，我们提供了单酰基甘油的证据脂肪酶（MAGL），将内源性大麻素2-芳基烯丙基甘油（2-AG）代谢的键酶大脑可能是AD的新治疗靶标。 MAGL的药理学失活减少了神经病理学并改善了TBI和AD动物模型中的突触可塑性和记忆形成。但是，我们这样做不知道MAGL的遗传破坏是否会产生与以下相似的有益效果 TBI中MAGL的药理抑制作用。另外，我们关于信号的知识存在差距介导TBI中MAGL抑制产生的抗炎和神经保护作用的途径。在这项竞争性续订应用，我们建议检验我们的假设，即减轻TBI诱导的AD样的假设 MAGL的药理或遗传破坏的神经病理学变化主要由星形胶质细胞中2-AG信号的增强，进而遏制神经炎症。因此，主要本应用中提出的研究的目的将使用我们既定的重复性小鼠模型闭合头部损伤证明了药理抑制或遗传学对2AG代谢的抑制作用 MAGL的破坏可以改善类似AD的神经病理学，改善突触和认知的恢复功能，并停止疾病的进展并描述介导有益的信号传导途径 MAGL抑制产生的影响。该项目的结果最终可能导致发展 TBI诱导的AD样神经退行性疾病的新型治疗干预措施。