Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the AβPPswe/PS1ΔE9 Mouse Model of Alzheimer's Disease
Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the AβPPswe/PS1ΔE9 Mouse Model of Alzheimer's Disease
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DOI：
10.3233/jad-131961
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发表时间：
2014-01-01
影响因子：
4
通讯作者：
Kendall, David A.
中科院分区：
文献类型：
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作者：
Maroof, Nazia;Ravipati, Srinivasarao;Kendall, David A.
内源性大麻素系统（ECS）的改变被认为在阿尔茨海默病（AD）中观察到的学习和记忆障碍中起作用。我们旨在确定AD的A β PPswe/PS1 Delta E9模型中脑ECS的状态。ECS包含神经调节性脂质内源性大麻素、大麻素和2-花生四烯酸甘油（2AG），其与G蛋白偶联的1型和2型大麻素受体相互作用。使用质谱法，我们定量了内源性大麻素水平，并评估了4-8个月大的野生型和A β PPswe/PS1 Delta E9小鼠的额叶皮质、海马和纹状体的脂质组学特征，以确定是否观察到内源性大麻素和脂质代谢的区域变化与年龄和疾病进展有关。此外，检查了旷场活动、情境恐惧条件反射任务中的表现以及评估空间和识别记忆的各种其他任务，以确定年龄和病理对这些参数的影响。在所有年龄段，A β PPswe/PS1 Delta E9小鼠在旷场和获得性情境恐惧中以及野生型小鼠中显著过度活跃，反映了完整的联想学习。然而，无论年龄大小，他们都表现出增强的背景恐惧记忆和减少的背景恐惧消退。在6和8月龄A β PPswe/PS1 Delta E9小鼠中观察到纹状体脂质代谢紊乱。两种基因型的海马和额叶皮质的内源性大麻素随年龄的增长而显着增加。8个月大的A β PPswe/PS1 Delta E9小鼠显示出比野生型小鼠显著更低的纹状体2AG水平，但更大的大麻素受体/效应器偶联。这项研究表明，随着A β PPswe/PS1 Delta E9小鼠年龄的增长，脂质代谢和内源性大麻素信号的变化也会发生，这可能有助于AD样行为缺陷的发展。
Alterations in the endocannabinoid system (ECS) are thought to play a role in learning and memory impairments observed in Alzheimer's disease (AD). We aimed to determine the status of the brain ECS in the A beta PPswe/PS1 Delta E9 model of AD. The ECS comprises the neuromodulatory lipid endocannabinoids, anandamide and 2-arachidonoyl glycerol (2AG), which interact with the G protein-coupled type-1 and type-2 cannabinoid receptors. Using mass spectrometry, we quantified endocannabinoid levels and assessed lipidomic profiles of the frontal cortex, hippocampus, and striatum of 4-8 month old wildtype and A beta PPswe/PS1 Delta E9 mice to determine whether regional variations in endocannabinoids and lipid metabolism are observed with age and disease progression. Additionally, open-field activity, performance in the contextual fear conditioning task, and various other tasks assessing spatial and recognition memory were examined to determine the influence of age and pathology on these parameters. At all ages, A beta PPswe/PS1 Delta E9 mice were significantly hyperactive in the open-field and acquired contextual fear as well as wildtype mice, reflecting intact associative learning. They, however, exhibited enhanced contextual fear memory and reduced contextual fear extinction regardless of age. Disturbances in striatal lipid metabolism were observed in 6 and 8 month old A beta PPswe/PS1 Delta E9 mice. Endocannabinoids increased significantly with age in the hippocampus and frontal cortex of both genotypes. 8 month old A beta PPswe/PS1 Delta E9 mice displayed significantly lower levels of striatal 2AG than wildtype mice, but greater cannabinoid receptor/effector coupling. This study shows that alterations in lipid metabolism and endocannabinoid signaling develop with age in A beta PPswe/PS1 Delta E9 mice, possibly contributing to the development of AD-like behavioral deficits.