A Protective role for 2-AG in age-dependent cognitive impairment.

2-AG 在年龄依赖性认知障碍中的保护作用。

基本信息

批准号：
9330759
负责人：
Daniele Piomelli
金额：
$ 19.31万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330759
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Acute Adult Affect Age Age-associated memory impairment Aging Animal Genetics Animal Model Animals Arachidonic Acids Brain Brain region CNR1 gene Cognition Cognitive Cognitive aging Cognitive deficits Data Dementia Dinoprostone Discrimination Dose Endocannabinoids Enzyme-Linked Immunosorbent Assay Enzymes Genetic Glial Fibrillary Acidic Protein Hippocampus (Brain)Impaired cognition Impairment Individual Inflammation Interleukin-1 beta Interleukin-6 Knock-in Laboratories Learning Ligands Lipids Location MAGL inhibitor Marijuana Measures Memory Memory impairment Modeling Molecular Analysis Molecular Target Monoacylglycerol Lipases Mus Mutant Strains Mice Odors Oral Oral Administration Oxidative Stress Performance Pharmaceutical Preparations Pharmacology Play Production Property Prosencephalon Prostaglandin D2 Protein Analysis Proteins Rattus Receptor Activation Receptor Signaling Research Reverse Transcriptase Polymerase Chain Reaction Role Route Severities Short-Term Memory Signal Transduction Synapses Synaptic plasticity System TNF gene Testing Variant Water Wild Type Mouse age related aged aging brain anandamide base behavior test cannabinoid receptor cognitive ability cognitive function cognitive performance cognitive testing endocannabinoid signaling endogenous cannabinoid system excitatory neuron excitotoxicity experimental study genetic manipulation improved innovation juvenile animal liquid chromatography mass spectrometry memory consolidation mouse model neuroinflammation novel novel strategies overexpression receptor relating to nervous system synaptic function time interval tool young adult

项目摘要

PROJECT SUMMARY Aging is accompanied by a decrease in cognitive ability, which can progress into cognitive impairment and dementia. Cannabinoid receptors, the molecular target of Δ9-THC in marijuana, modulate long- and short-term synaptic plasticity at many central synapses. In young mice and rats, pharmacological activation of these receptors impairs memory, whereas blockade exerts pro-cognitive effects. The opposite occurs, however, in aged animals, in which cannabinoid receptor activation alleviates, whereas genetic cannabinoid receptor deletion enhances, aging-related cognitive deficits. Several possible mechanisms have been proposed to explain how cannabinoid receptor signaling might differentially influence cognitive function in young and old animals, but very limited data are available about the role played by endocannabinoid ligands such as 2- arachidonoyl-sn-glycerol (2-AG) and anandamide. In preliminary studies, we found that 2-AG production is impaired in the hippocampus of 18- and 21-month old mice, compared to 12-month old mice. Based on this finding, we hypothesize that age-dependent reductions in 2-AG mobilization (formation and/or deactivation) contribute to cognitive aging. We have two Specific Aims that are relevant to a test of this hypothesis. Aim 1. Effects of reduced forebrain 2-AG mobilization on cognitive aging. We have generated mice that overexpress the 2-AG-hydrolyzing enzyme, monoacylglycerol lipase (MGL), in excitatory neurons of the forebrain (MGL-tg mice). This genetic manipulation reduces forebrain 2-AG levels without altering expression of cannabinoid receptors or endocannabinoid-related proteins and lipids. This model is unique in that it does not display the compensatory changes seen in knock-out mouse models that lack the ability to produce or degrade 2-AG. Using MGL-tg mice, we will ask whether forebrain 2-AG signaling is involved in cognitive aging. We will compare MGL-tg and wild-type mice – aged 2 , 5, 12 and 18 months – for three key parameters: Study 1.1. Forebrain 2-AG signaling; Study 1.2. Cognitive performance; and, Study 1.3. Markers of neural inflammation. Aim 2. Effects of enhanced forebrain 2-AG mobilization on cognitive aging. If decreased 2-AG signaling contributes to cognitive aging, then pharmacological correction of this deficit should ameliorate cognition in old animals. We will determine whether subchronic oral administration of the compound NF1819, a novel MGL inhibitor with favorable drug-like properties, improves age-related cognitive deficits in MGL-tg and wild-type mice. In a first experiment (Study 2.1), we will determine the optimal dosing of NF1819, and in a subsequent experiment (Study 2.2), we will administer NF1819 for 30 days or 90 days to MGL-tg mice and wild-type controls, testing cognitive performance and neuroinflammatory markers. The project has the potential to uncover new functions of 2-AG signaling in the aging brain, and to lay the groundwork for the discovery of novel strategies to alleviate age-related cognitive deficits.

项目概要衰老伴随着认知能力的下降，这可能会发展为认知障碍和大麻素受体是大麻中 Δ9-THC 的分子靶标，可调节长期和短期。在年轻小鼠和大鼠中，许多中央突触的突触可塑性，这些突触的药理激活。然而，受体会损害记忆，而封锁则会产生促认知作用。老年动物，其中大麻素受体激活减轻，而遗传大麻素受体已经提出了几种可能的机制来增强与衰老相关的认知缺陷。解释大麻素受体信号如何不同地影响年轻人和老年人的认知功能动物，但有关内源性大麻素配体（例如 2- 花生四烯酰-sn-甘油 (2-AG) 和花生四烯酸乙醇胺在初步研究中，我们发现 2-AG 的产生是与 12 个月大的小鼠相比，18 个月和 21 个月大的小鼠的海马体受损。研究发现，我们追求年龄依赖性的 2-AG 动员（形成和/或失活）减少我们有两个与目标 1 的检验相关的具体目标。前脑 2-AG 动员减少对认知衰老的影响我们已经培育出了过度表达的小鼠。前脑兴奋性神经元中的 2-AG 水解酶、单酰基甘油脂肪酶 (MGL)（MGL-tg 小鼠），这降低了基因操作前脑 2-AG 水平，而不改变大麻素的表达。该模型的独特之处在于它不显示受体或内源性大麻素相关的蛋白质和脂质。在缺乏产生或降解 2-AG 能力的基因敲除小鼠模型中观察到的代偿性变化。我们将使用 MGL-tg 小鼠来探究前脑 2-AG 信号传导是否与认知衰老有关。比较 MGL-tg 和野生型小鼠（2、5、12 和 18 个月）的三个关键参数：研究 1.1。前脑 2-AG 信号；研究 1.2；以及研究 1.3。目标 2. 增强前脑 2-AG 动员对认知衰老的影响（如果 2-AG 信号传导减弱）。导致认知衰老，那么通过药物纠正这种缺陷应该可以改善老年人的认知能力我们将确定化合物 NF1819（一种新型 MGL）是否可以亚慢性口服给药。具有良好的药物样特性的抑制剂，可改善 MGL-tg 和野生型中与年龄相关的认知缺陷在第一个实验（研究 2.1）中，我们将确定 NF1819 的最佳剂量，并在随后的实验中确定。实验（研究2.2），我们将给MGL-tg小鼠和野生型小鼠施用NF1819 30天或90天该项目有潜力进行控制、测试认知表现和神经炎症标记物。揭示衰老大脑中 2-AG 信号传导的新功能，并为发现缓解与年龄相关的认知缺陷的新策略。