Hock Brian J, Lattal K Matthew, Kulnane Laura Shapiro, Abel Ted, Lamb Bruce T
Department of Psychology, Austin Peay State University, Clarksville, TN, 37044 USA.
Curr Aging Sci. 2009 Dec;2(3):205-13. doi: 10.2174/1874609810902030205.
To gain insight into the relationship between pathological alterations and memory deficits observed in Alzheimer's disease (AD), a number of amyloid precursor protein (APP) transgenic animal models have been generated containing familial AD mutations. The most commonly utilized method involves a cDNA-based approach, utilizing heterologous promoters to drive expression of specific APP isoforms. As a result of the assumptions inherent in the design of each model, the different cDNA-based transgenic mouse models have revealed different relationships between the biochemical, pathological and behavioral alterations observed in these models. Here we provide further characterization of a genomic-based, amyloid precursor protein yeast artificial chromosome transgenic mouse model of AD, R1.40, that makes few assumptions regarding disease pathogenesis to study the relationship between brain pathology and altered behavior. Aged R1.40 transgenic and control mice were tested for learning and memory in the Morris water maze and for working memory in the Y maze. Results from the water maze demonstrated intact learning in the both control and R1.40 mice, but impairments in the long-term retention of this information in the transgenic mice, but not controls. Interestingly, however, long-term memory deficits did not correlate with the presence of Abeta deposits within the group of animals examined. By contrast, age-related working memory impairments were also observed in the Y maze in the R1.40 mice, and these deficits correlated with the presence of Abeta deposits. Our results demonstrate unique behavioral alterations in the R1.40 mouse model of AD that are likely both dependent and independent of Abeta deposition.
为深入了解阿尔茨海默病（AD）中观察到的病理改变与记忆缺陷之间的关系，已构建了多种含有家族性AD突变的淀粉样前体蛋白（APP）转基因动物模型。最常用的方法是基于cDNA的方法，利用异源启动子驱动特定APP异构体的表达。由于每个模型设计中固有的假设，不同的基于cDNA的转基因小鼠模型揭示了这些模型中观察到的生化、病理和行为改变之间的不同关系。在此，我们进一步描述了一种基于基因组的AD淀粉样前体蛋白酵母人工染色体转基因小鼠模型R1.40，该模型对疾病发病机制的假设较少，用于研究脑病理学与行为改变之间的关系。对老年R1.40转基因小鼠和对照小鼠进行了Morris水迷宫中的学习和记忆测试以及Y迷宫中的工作记忆测试。水迷宫实验结果表明，对照小鼠和R1.40小鼠的学习能力均正常，但转基因小鼠在长期保留这些信息方面存在缺陷，而对照小鼠则没有。然而，有趣的是，在所检查的动物群体中，长期记忆缺陷与Aβ沉积物的存在无关。相比之下，在Y迷宫中也观察到R1.40小鼠存在与年龄相关的工作记忆损伤，且这些缺陷与Aβ沉积物的存在相关。我们的结果表明，AD的R1.40小鼠模型存在独特的行为改变，这些改变可能既依赖于Aβ沉积，也独立于Aβ沉积。
