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

项目总结 衰老伴随着认知能力的下降，这可能会进展为认知障碍和 痴呆症。大麻中Δ9-THC的分子靶标大麻素受体调节长期和短期 许多中枢突触的突触可塑性。在幼年小鼠和大鼠中，这些药物的激活 受体会损害记忆，而阻断则会发挥促进认知的作用。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来 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，但关于内源性大麻素配体所起作用的数据非常有限，如2- 花生四烯酰甘油(2-AG)和花生胺。在初步研究中，我们发现2-AG的产量是 与12月龄小鼠相比，18月龄和21月龄小鼠的海马区受损。在此基础上 发现，我们假设2-AG动员(形成和/或失活)随年龄而减少 会导致认知老化。我们有两个与检验这一假说相关的具体目标。目标1。 前脑2-AG活动减少对认知老化的影响。我们已经产生了过度表达的小鼠 前脑兴奋性神经元中的2-氨基丁酸水解酶--单酰甘油脂肪酶(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类。此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看到的代偿性变化。 利用MGL-TG小鼠，我们将询问前脑2-AG信号是否参与认知衰老。我们会 比较MGL-TG和野生型小鼠--2、5、12和18个月大的小鼠--三个关键参数：研究1.1。 前脑2-AG信号；研究1.2。认知表现；和研究1.3。神经炎症的标记物。 目的2.增强前脑2-AG动员对认知衰老的影响。IF减少2-AG信令 会导致认知老化，那么对这种缺陷的药物纠正应该会改善老年人的认知 动物。我们将确定亚慢性口服复方NF1819，一种新型的MGL 具有良好的类药物特性的抑制剂，改善MGL-TG和野生型的年龄相关认知障碍 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)，给MGL-TG小鼠和野生型小鼠分别给予30天或90天的NF1819 对照组，测试认知表现和神经炎性标志物。该项目有可能 揭示2-AG信号在衰老脑中的新功能，为发现2-AG信号通路奠定基础 缓解与年龄相关的认知缺陷的新策略。

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.