Kishimoto Yasushi, Fukumoto Kai, Nagai Mika, Mizuguchi Ayaka, Kobashi Yuiko
Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan.
Int J Alzheimers Dis. 2017;2017:8584205. doi: 10.1155/2017/8584205. Epub 2017 Nov 27.
Presenilin 1 and presenilin 2 (PS1 and PS2) play a critical role in -secretase-mediated cleavage of amyloid- precursor protein (APP) and the subsequent generation of -amyloid peptides. The purpose of the present study was to test whether PS2 mutation accelerates the onset of contextual fear memory deficits in a mouse model of AD that expresses a mutation (K670N/M671L) of the human APP with the Swedish mutation (Tg2576 mice). In the present study, an APP/PS2 double-transgenic mouse model (PS2Tg2576) was generated by crossbreeding transgenic mice carrying the human mutant PS2 (N141I) with Tg2576 mice. Contextual fear conditioning was tested in PS2Tg2576 mice aged 3, 4, 6, and 10-12 months. PS2Tg2576 mice showed a tendency of lower freezing behavior as early as 3 months of age, but significant memory impairment was observed from the age of 4 months. The cognitive impairment was more prominent at ages of 6 and 10-12 months. In contrast, Tg2576 mice aged 3 and 4 months exhibited successful acquisition of contextual fear learning, but Tg2576 mice aged 6 months or older showed significantly impaired fear memory. These results show that PS2 mutation significantly accelerates the onset of fear memory deficits in the APP AD model mice.
早老素1和早老素2（PS1和PS2）在β-分泌酶介导的淀粉样前体蛋白（APP）切割以及随后的β-淀粉样肽生成过程中发挥着关键作用。本研究的目的是测试在表达带有瑞典突变的人类APP突变（K670N/M671L）的阿尔茨海默病小鼠模型（Tg2576小鼠）中，PS2突变是否会加速情境恐惧记忆缺陷的出现。在本研究中，通过将携带人类突变PS2（N141I）的转基因小鼠与Tg2576小鼠杂交，构建了APP/PS2双转基因小鼠模型（PS2Tg2576）。对3、4、6和10 - 12月龄的PS2Tg2576小鼠进行了情境恐惧条件反射测试。PS2Tg2576小鼠早在3月龄时就表现出较低的僵住行为倾向，但在4月龄时观察到明显的记忆障碍。在6月龄和10 - 12月龄时，认知障碍更为明显。相比之下，3和4月龄的Tg2576小鼠能够成功获得情境恐惧学习能力，但6月龄及以上的Tg2576小鼠表现出明显受损的恐惧记忆。这些结果表明，PS2突变显著加速了APP阿尔茨海默病模型小鼠恐惧记忆缺陷的出现。
