Behavioral phenotyping of GFAP-ApoE3 and-ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology
Behavioral phenotyping of GFAP-ApoE3 and-ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology
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DOI：
10.1006/exnr.2001.7715
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Hartman, RE;Wozniak, DF;Holtzman, DM
为了研究脑内产生的不同人载脂蛋白E（apoE）同种型的潜在神经行为效应，产生转基因（TG）小鼠，其中人apoE 3或apoE 4同种型在星形胶质细胞特异性胶质细胞酸性蛋白启动子的控制下，并且将这些TG小鼠培育回apoE敲除（KO）小鼠。apoE 3和apoE 4 TG小鼠的行为表型通过进行纵向研究得出，其中apoE 3和apoE 4 TG小鼠与apoE KO和野生型（WT）小鼠（均为雄性）在几种行为测量上进行比较。分析自发活动，“开放领域”的行为，声惊吓/前脉冲抑制，和高架十字迷宫数据表明，apoE TG/KO组比WT小鼠更“情绪反应性”，apoE 4小鼠通常是最具反应性的。各组之间在旋转孔板和水上导航任务上没有表现差异，表明apoE TG/KO小鼠的参考记忆处理完整。然而，apoE 4小鼠在径向臂迷宫（11-14个月）中基于工作记忆的方案严重受损。非关联因素（感觉运动能力或情感差异）似乎没有混淆的学习/记忆结果的解释。蛋白质印迹分析显示新皮质或海马中突触、神经元或神经胶质标记物的水平没有改变，组织学分析显示apoE KO/TG小鼠中没有A β沉积或神经炎斑块的证据。我们的研究结果表明，apoE 4在大脑中的表达可能有选择性的有害影响记忆功能的典型阿尔茨海默氏症样神经病理学的情况下。(C)北京：科学出版社.
For the purpose of studying the potential neurobehavioral effects of different human apolipoprotein E (apoE) isoforms produced within the brain, transgenic (TG) mice were generated in which human apoE3 or apoE4 isoforms were under control of an astrocyte-specific, glial fibrillary acidic protein promoter and these TG mice were bred back to apoE knockout (KO) mice. Behavioral phenotypes of apoE3 and apoE4 TG mice were derived by conducting a longitudinal study in which apoE3 and apoE4 TG mice were compared with apoE KO and wild-type (WT) mice (all male) on several behavioral measures. Analysis of locomotor activity, "open-field" behaviors, acoustic startle/prepulse inhibition, and elevated plus maze data suggested that the apoE TG/KO groups were more "emotionally reactive" than WT mice, with apoE4 mice typically being the most reactive. The absence of performance differences among groups on the rotating holeboard and water navigation tasks suggested intact reference memory processing in apoE TG/KO mice. However, apoE4 mice were profoundly impaired on a working memory-based protocol in the radial arm maze (11-14 months). Nonassociative factors (sensorimotor capacities or emotionality differences) did not appear to confound interpretation of the learning/memory results. Western blot analysis revealed no alterations in the level of synaptic, neuronal, or glial markers in neocortex or hippocampus and histologic analysis revealed no evidence of A beta deposition or neuritic plaques in the apoE KO/TG mice. Our findings suggest that apoE4 expression in the brain may have selective deleterious effects on memory function in the absence of typical Alzheimer's-like neuropathology. (C) 2001 Academic Press.