Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern
Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern
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DOI：
10.1016/j.neuroscience.2006.05.001
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Andreasson, K. I.
中科院分区：
文献类型：
--
作者：
Melnikova, T.;Savonenko, A.;Andreasson, K. I.
服用非类固醇抗炎药可降低正常老龄化人群中患阿尔茨海默病的风险，这一效果可能是由于抑制了环氧合酶，环氧合酶是前列腺素形成的限速酶。在这项研究中，我们研究了环氧合酶-2(COX-2)活性的增加是否促进了阿尔茨海默病转基因小鼠模型的疾病进展。为了研究COX-2活性的功能效应，对雄性和雌性双基因小鼠(瑞典突变的淀粉样前体蛋白[APPsWE]-缺失外显子9的早老素-1蛋白[PS1dE9]和三致性COX-2/APPsWE-PS1dE9)进行了选择性COX-2抑制剂塞来昔布+/-给药的行为测试。行为测试包括测量空间工作和识别记忆的三次Y形迷宫，以及测试多动症水平的开放现场任务。在APPSwePS1dE9小鼠中过表达COX-2导致雌性小鼠空间工作记忆的特异性缺陷，而雄性小鼠则没有。通过药物抑制COX-2活性，这些性别特异性缺陷被消除。重要的是，COX-2相关缺陷依赖于所有三个转基因基因的共同表达，因为COX-2单一转基因和APPsWE-PS1dE9双基因小鼠表现出正常的记忆。对淀粉样斑块负荷和总Aβ40和42肽的量化显示，使用赋形剂或塞来昔布治疗的三生性和双生性小鼠没有显著差异。综上所述，这些数据表明，在淀粉样蛋白负荷没有显著变化的情况下，COX-2和Aβ多肽对认知的影响之间存在交互作用，这种交互作用是以性别特有的方式发生的。这些发现表明，COX-2的病理性激活可能会增强Aβ多肽的毒性，特别是对女性，而不会显著影响Aβ的蓄积。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/ APPswe-PS1dE9) were behaviorally tested +/- administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswePS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total A beta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and A beta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of A beta peptides, particularly in females, without significantly affecting A beta accumulation. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.