Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition
Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition
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尽管淀粉样蛋白沉积减少，但阿尔茨海默氏病小鼠模型中大麻素受体 1 缺陷导致认知障碍增强
DOI：
10.1016/j.neurobiolaging.2013.05.027
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发表时间：
2013
影响因子：
4.2
通讯作者：
A.B. Clement
中科院分区：
文献类型：
--
作者：
C. Stumm;C. Hiebel;R. Hanstein;M. Purrio;H. Nagel;A. Conrad;B. Lutz;C. Behl;A.B. Clement
阿尔茨海默病（AD）的特征在于淀粉样蛋白-β沉积在淀粉样蛋白斑块中、神经元缠结、炎症、神经元损失和认知缺陷。大麻素显示神经调节和神经保护作用，并影响记忆获得。在这里，我们研究了大麻素受体1型（CB 1）缺陷对AD病理学发展的影响，通过饲养淀粉样前体蛋白（APP）瑞典突变小鼠（APP 23），AD动物模型，CB 1缺陷小鼠。除了APP 23/CB 1 −/−小鼠的体重较低外，这些小鼠中的大多数在典型的AD相关变化变得明显之前死亡。存活的小鼠显示APP及其片段的量减少，表明CB 1对APP加工的调节影响，这通过调节CB 1在体外的表达得到证实。APP水平降低伴随着APP 23/CB 1 −/−小鼠中斑块负荷减少和炎症减少。然而，与具有完整CB 1的APP 23小鼠相比，APP 23/CB 1 −/−小鼠表现出受损的学习和记忆缺陷。这些数据反对淀粉样蛋白斑块负荷与缺乏CB 1的AD小鼠模型中的认知能力的直接相关性。此外，研究结果表明，CB 1缺乏会加重AD相关的认知缺陷，并支持CB 1作为药理学靶点的潜在作用。
Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1−/−mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression in vitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1−/−mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1−/−mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.
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影响因子：
4.9
作者：
Eubanks, Lisa M.;Rogers, Claude J.;Janda, Kim D.
通讯作者：
Janda, Kim D.
影响因子：
3.9
作者：
Asuni, Ayodeji A.;Perry, V. Hugh;O'Connor, Vincent
通讯作者：
O'Connor, Vincent
影响因子：
44.1
作者：
Teng, Lin;Zhao, Jian;Pei, Gang
通讯作者：
Pei, Gang
阿尔茨海默病药物发现进展：更新。
影响因子：
--
作者：
Michael Williams
通讯作者：
Michael Williams
影响因子：
2.5
作者：
Milton, NGN
通讯作者：
Milton, NGN