Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks
Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks
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DOI：
10.1016/j.bbr.2008.05.008
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发表时间：
2008-11-21
影响因子：
2.7
通讯作者：
Mathis, Chantal
中科院分区：
文献类型：
--
作者：
Bour, Alexandra;Grootendorst, Jeannette;Mathis, Chantal
载脂蛋白（apo）E4是人类三种载脂蛋白E（h - apoE）异构体之一，已被确定为阿尔茨海默病以及与衰老相关的认知缺陷的主要遗传风险因素。然而，载脂蛋白E在学习和记忆过程中的生物学机制尚不清楚。在人类载脂蛋白E靶向替代（TR）小鼠中研究了载脂蛋白E在认知过程中可能存在的异构体依赖性作用。这些小鼠在内源性小鼠载脂蛋白E调控序列的控制下表达人类载脂蛋白E3或载脂蛋白E4基因，导致h - apoE在时间和空间模式上的生理表达与人类相似。对雄性和雌性载脂蛋白E3 - TR、载脂蛋白E4 - TR、载脂蛋白E基因敲除以及C57BL / 6J小鼠（15 - 18个月）进行空间记忆和回避条件反射任务测试。与载脂蛋白E3 - TR小鼠相比，雌性载脂蛋白E4 - TR小鼠的空间记忆受损，这基于它们在以下方面表现不佳：（i）水迷宫参考记忆任务的探测测试，（ii）水迷宫工作记忆任务，以及（iii）主动回避Y型迷宫任务。载脂蛋白E4 - TR小鼠在被动回避任务中的保持能力也受损，但其他基因型小鼠未出现这种情况。空间记忆和回避记忆任务中的这些缺陷可能与先前在载脂蛋白E4 - TR小鼠的海马体和杏仁核中报道的解剖学和功能异常有关。我们得出结论，载脂蛋白E4 - TR小鼠为理解载脂蛋白E4依赖性认知衰退易感性的潜在机制提供了一个极好的模型。（C）2008爱思唯尔有限公司。保留所有权利。
Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline. (C) 2008 Elsevier B.V. All rights reserved.