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。

• 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
• 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

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 失智。大麻素受体是大麻中 Δ9-THC 的分子靶标，可调节长期和短期 许多中央突触的突触可塑性。在幼年小鼠和大鼠中，这些药物的药理学激活 受体会损害记忆，而阻断则会产生促认知作用。然而，相反的情况发生在 老年动物，其中大麻素受体激活减轻，而遗传大麻素受体 缺失会增强与衰老相关的认知缺陷。已经提出了几种可能的机制 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- 花生四烯酸-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 的产量是 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。基于此 根据这一发现，我们假设 2-AG 动员（形成和/或失活）的年龄依赖性减少 有助于认知老化。我们有两个与检验该假设相关的具体目标。目标1。 前脑 2-AG 动员减少对认知衰老的影响。我们已经培育出过度表达的小鼠 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 老鼠）。这种基因操作降低了前脑 2-AG 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。该模型的独特之处在于它不显示 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。 使用 MGL-tg 小鼠，我们将探究前脑 2-AG 信号传导是否与认知衰老有关。我们将 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信号传导；研究1.2。认知表现；以及研究 1.3。神经炎症的标志物。 目标 2. 增强前脑 2-AG 动员对认知衰老的影响。如果 2-AG 信号传导减少 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 动物。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 老鼠。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 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 控制，测试认知表现和神经炎症标记物。该项目有潜力 揭示 2-AG 信号在衰老大脑中的新功能，并为发现 缓解与年龄相关的认知缺陷的新策略。