Savonenko Alena, Xu Guilian M, Melnikova Tatiana, Morton Johanna L, Gonzales Victoria, Wong Molly P F, Price Donald L, Tang Fai, Markowska Alicja L, Borchelt David R
Department of Pathology, Johns Hopkins School of Medicine, Ross Building, Room 558, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Neurobiol Dis. 2005 Apr;18(3):602-17. doi: 10.1016/j.nbd.2004.10.022.
Transgenic mice made by crossing animals expressing mutant amyloid precursor protein (APPswe) to mutant presenilin 1 (PS1dE9) allow for incremental increases in Abeta42 production and provide a model of Alzheimer-type amyloidosis. Here, we examine cognition in 6- and 18-month old transgenic mice expressing APPswe and PS1dE9, alone and in combination. Spatial reference memory was assessed in a standard Morris Water Maze task followed by assessment of episodic-like memory in Repeated Reversal and Radial Water maze tasks. We then used factor analysis to relate changes in performance in these tasks with cholinergic markers, somatostatin levels, and amyloid burden. At 6 months of age, APPswe/PS1dE9 double-transgenic mice showed visible plaque deposition; however, all genotypes, including double-transgenic mice, were indistinguishable from nontransgenic animals in all cognitive measures. In the 18-month-old cohorts, amyloid burdens were much higher in APPswe/PS1dE9 mice with statistically significant but mild decreases in cholinergic markers (cortex and hippocampus) and somatostatin levels (cortex). APPswe/PS1dE9 mice performed all cognitive tasks less well than mice from all other genotypes. Factor and correlation analyses defined the strongest correlation as between deficits in episodic-like memory tasks and total Abeta loads in the brain. Collectively, we find that, in the APPswe/PS1dE9 mouse model, some form of Abeta associated with amyloid deposition can disrupt cognitive circuits when the cholinergic and somatostatinergic systems remain relatively intact; and that episodic-like memory seems to be more sensitive to the toxic effects of Abeta.
通过将表达突变淀粉样前体蛋白（APPswe）的动物与突变早老素1（PS1dE9）杂交制备的转基因小鼠，可使β淀粉样蛋白42（Aβ42）的产生逐渐增加，并提供了一种阿尔茨海默病型淀粉样变性的模型。在此，我们研究了6个月和18个月大的单独或联合表达APPswe和PS1dE9的转基因小鼠的认知情况。在标准的莫里斯水迷宫任务中评估空间参考记忆，随后在重复反转和放射状水迷宫任务中评估情景样记忆。然后，我们使用因子分析将这些任务中的行为表现变化与胆碱能标记物、生长抑素水平和淀粉样蛋白负荷联系起来。6个月大时，APPswe/PS1dE9双转基因小鼠出现可见的斑块沉积；然而，在所有认知测量中，所有基因型，包括双转基因小鼠，与非转基因动物没有区别。在18个月大的队列中，APPswe/PS1dE9小鼠的淀粉样蛋白负荷要高得多，胆碱能标记物（皮质和海马体）和生长抑素水平（皮质）有统计学意义但轻微下降。APPswe/PS1dE9小鼠在所有认知任务中的表现都比所有其他基因型的小鼠差。因子分析和相关性分析确定最强的相关性存在于情景样记忆任务缺陷与大脑中总Aβ负荷之间。总体而言，我们发现，在APPswe/PS1dE9小鼠模型中，当胆碱能和生长抑素能系统相对完整时，与淀粉样蛋白沉积相关的某种形式的Aβ可破坏认知回路；并且情景样记忆似乎对Aβ的毒性作用更敏感。
