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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

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.

总结