Edwards Stephen R, Hamlin Adam S, Marks Nicola, Coulson Elizabeth J, Smith Maree T
Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Qld, Australia.
Clin Exp Pharmacol Physiol. 2014 Oct;41(10):798-806. doi: 10.1111/1440-1681.12277.
Evaluation of the efficacy of novel therapeutics for potential treatment of Alzheimer's disease (AD) requires an animal model that develops age-related cognitive deficits reproducibly between independent groups of investigators. Herein we assessed comparative temporal changes in spatial memory function in two commercially available transgenic mouse models of AD using the Morris water maze (MWM), incorporating both visible and hidden platform training. Individual cohorts of cDNA-based 'line 85'-derived double-transgenic mice coexpressing the 'Swedish' mutation of amyloid precursor protein (APPSwe) and the presenillin 1 (PS1) 'dE9' mutation were assessed in the MWM at mean ages of 3.6, 9.3 and 14.8 months. We found significant deficits in spatial memory retention in APPSwe/PS1dE9 mice aged 3.6 months and robust deficits in spatial memory acquisition and retention in APPSwe/PS1dE9 mice aged 9.3 months, with a further significant decline by age 14.8 months. β-Amyloid deposits were present in brain sections by 7.25 months of age. In contrast, MWM studies with individual cohorts (aged 4-21 months) of single-transgenic genomic-based APPSwe mice expressing APPSwe on a yeast artificial chromosomal (YAC) construct showed no significant deficits in spatial memory acquisition until 21 months of age. There were no significant deficits in spatial memory retention up to 21 months of age and β-amyloid deposits were not present in brain sections up to 24 months of age. These data, generated using comprehensive study designs, show that APPSwe/PS1dE9 but not APPSwe YAC mice appear to provide a suitably robust model of AD for efficacy assessment of novel AD treatments in development.
评估新型疗法对阿尔茨海默病（AD）潜在治疗效果需要一种动物模型，该模型能在不同独立研究团队之间可重复地产生与年龄相关的认知缺陷。在此，我们使用莫里斯水迷宫（MWM），结合可见和隐藏平台训练，评估了两种市售AD转基因小鼠模型中空间记忆功能的比较性时间变化。对基于cDNA的“85系”双转基因小鼠个体队列进行了评估，这些小鼠共表达淀粉样前体蛋白（APPSwe）的“瑞典”突变和早老素1（PS1）的“dE9”突变，在MWM中评估时的平均年龄分别为3.6、9.3和14.8个月。我们发现，3.6个月大的APPSwe/PS1dE9小鼠在空间记忆保持方面存在显著缺陷，9.3个月大的APPSwe/PS1dE9小鼠在空间记忆获取和保持方面存在明显缺陷，到14.8个月大时进一步显著下降。β-淀粉样蛋白沉积在7.25个月大时出现在脑切片中。相比之下，对基于基因组的单转基因APPSwe小鼠个体队列（4 - 21个月大）进行的MWM研究表明，在酵母人工染色体（YAC）构建体上表达APPSwe的小鼠直到21个月大时在空间记忆获取方面均无显著缺陷。在21个月大之前空间记忆保持方面没有显著缺陷，并且直到24个月大时脑切片中都没有β-淀粉样蛋白沉积。这些使用综合研究设计产生的数据表明，APPSwe/PS1dE9小鼠而非APPSwe YAC小鼠似乎为评估新型AD治疗药物的疗效提供了一个足够强大的AD模型。
