Zhuo Jia-Min, Prakasam Annamalai, Murray Melissa E, Zhang Hai-Yan, Baxter Mark G, Sambamurti Kumar, Nicolle Michelle M
Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Curr Alzheimer Res. 2008 Aug;5(4):385-91. doi: 10.2174/156720508785132280.
The medial temporal lobe-dependent memory loss associated with Alzheimer's disease (AD) is often accompanied by a loss of prefrontal cortex-dependent cognitive domains that fall under the broad category of executive function. In this study, we examined the relationship between one type of prefrontal-dependent executive function, discrimination reversal-learning, and levels of the amyloid beta protein (Abeta) of 40 and 42 residues in a transgenic mouse model (Tg2576) of the over-expression of the familial AD mutant form of the amyloid precursor protein (APPsw). Tg2576 and their non-transgenic (NTg) littermates were assessed at 3 and 6 months of age when there is little to no amyloid plaque deposition. After reversal-learning assessment, Abeta40 and Abeta42 were quantified in the prefrontal cortex and hippocampus. Tg2576 mice were impaired in reversal-learning at 6 but not 3 months of age when compared to the NTg group. Coincidently, there was a corresponding approximately 3-fold increase of Abeta42 levels in the prefrontal cortex of 6- compared to 3-month-old Tg2576 mice. In addition, the prefrontal cortex contained higher levels of Abeta42 compared to the hippocampus at both 3 and 6 months of age, regardless of genotype, indicating a high vulnerability of this brain region to Abeta42 accumulation. These data suggest that the early emergence of reversal-learning deficits in the Tg2576 mouse may be due to the localized increase of Abeta42 in the prefrontal cortex.
与阿尔茨海默病（AD）相关的内侧颞叶依赖性记忆丧失，通常伴随着前额叶皮质依赖性认知领域的丧失，这些认知领域属于执行功能这一广泛类别。在本研究中，我们在淀粉样前体蛋白（APPsw）家族性AD突变形式过表达的转基因小鼠模型（Tg2576）中，研究了一种前额叶依赖性执行功能——辨别逆转学习，与40和42个残基的淀粉样β蛋白（Aβ）水平之间的关系。在3个月和6个月大时评估Tg2576及其非转基因（NTg）同窝小鼠，此时几乎没有淀粉样斑块沉积。在逆转学习评估后，对前额叶皮质和海马中的Aβ40和Aβ42进行定量。与NTg组相比，Tg2576小鼠在6个月大时逆转学习受损，但在3个月大时未受损。巧合的是，与3个月大的Tg2576小鼠相比，6个月大的Tg2576小鼠前额叶皮质中的Aβ42水平相应增加了约3倍。此外，无论基因型如何，在3个月和6个月大时，前额叶皮质中的Aβ42水平均高于海马，这表明该脑区对Aβ42积累高度敏感。这些数据表明，Tg2576小鼠中逆转学习缺陷的早期出现可能是由于前额叶皮质中Aβ42的局部增加。
