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.

项目摘要衰老是通过降低认知能力来实现的，这可以发展为认知障碍和失智。大麻素受体是大麻中δ-THC的分子靶标，可调节长期和短期许多中央突触处的突触可塑性。在年轻的小鼠和大鼠中，这些药物激活受体会损害记忆，而封锁执行促进认知效果。但是，相反的发生在老化动物，其中大麻素受体的激活减轻了，而遗传大麻素受体删除增强了与衰老相关的认知缺陷。已经提出了几种可能的机制说明大麻素受体信号如何对年轻人和老年人的认知功能有所不同动物，但有关内源性大麻素配体（例如2-）起作的作用的数据非常有限 Arachidonoyl-SN-甘油（2-AG）和anandamide。在初步研究中，我们发现2-AG产生是与12个月大的小鼠相比，在18岁和21个月大的小鼠的海马受损。基于此发现，我们假设在2个动员中依赖年龄的减少（形成和/或停用）有助于认知衰老。我们有两个与该假设的检验有关的具体目标。目标1。降低前脑2 ag动员对认知衰老的影响。我们已经产生了过表达的小鼠前脑兴奋性神经元（MGL-TG 小鼠）。这种遗传操作可降低前脑2AG水平，而不改变大麻素的表达受体或内源性大麻素相关的蛋白质和脂质。该模型是唯一的，因为它不显示补偿性变化参见缺乏产生或降解2-AG的能力的基因敲除小鼠模型。使用MGL-TG小鼠，我们将询问前脑2 AG信号是否参与认知衰老。我们将比较MGL-TG和野生型小鼠 - 年龄在2、5、12和18个月之间 - 有关三个关键参数：研究1.1。前脑2-ag信号传导；研究1.2。认知表现；并且，研究1.3。神经炎症的标记。目标2。增强前脑2-AG动员对认知衰老的影响。如果降低2-ag信号传导有助于认知衰老，然后对这种赤字的药物纠正应改善旧认知动物。我们将确定化合物NF1819的亚慢性口服施用是一种新型MGL 具有良好药物样特性的抑制剂，改善与年龄相关的认知定义在MGL-TG和野生型中的定义老鼠。在第一个实验（研究2.1）中，我们将确定NF1819的最佳剂量，然后实验（研究2.2），我们将向MGL-TG小鼠和野生型施用NF1819 30天或90天对照，测试认知性能和神经炎症标记。该项目有潜力发现衰老大脑中2-ag信号的新功能，并为发现奠定基础减轻与年龄相关的认知缺陷的新型策略。