Apolipoprotein E Isoform-Dependent Effects on Human Amyloid Precursor Protein/Aβ-Induced Behavioral Alterations and Cognitive Impairments and Insoluble Cortical Aβ42 Levels.
Apolipoprotein E Isoform-Dependent Effects on Human Amyloid Precursor Protein/Aβ-Induced Behavioral Alterations and Cognitive Impairments and Insoluble Cortical Aβ42 Levels.
复制标题
载脂蛋白E同工型依赖性对人淀粉样蛋白蛋白/Aβ诱导的行为改变和认知障碍以及不溶性皮质Aβ42水平的作用。
DOI：
10.3389/fnagi.2022.767558
复制
发表时间：
2022
影响因子：
4.8
通讯作者：
Raber J
中科院分区：
文献类型：
--
作者：
Holden S;Kundu P;Torres ERS;Sudhakar R;Krenik D;Grygoryev D;Turker MS;Raber J
表达人淀粉样蛋白前体蛋白（APP）的小鼠含有显性瑞典和伊比利亚突变（AppNL-F）或北极突变（AppNL-G-F），分别在18和6个月大的小鼠模型中显示出与阿尔茨海默病（AD）相关的神经病理学和海马依赖性认知障碍。载脂蛋白E参与胆固醇代谢，在维持大脑功能方面起着重要作用。人载脂蛋白E有三种亚型：E2、E3和E4。与E3相比，E4增加，而E2保护AD风险。在6个月龄时，在斑块病理学发生之前，E3而不是E4在Morris水迷宫中对hAPP/Aβ诱导的空间记忆保持障碍具有保护作用。然而，这些早期的研究是有限的，因为hapoE不在脑外表达，E3或E4不在apoE启动子的控制下表达，E2通常不包括在内，hAPP是转基因过表达的，小鼠和hAPP都存在。因此，为了确定apoE是否对6月龄和18月龄的成年雌性和雄性小鼠中hAPP/Aβ诱导的行为改变和认知障碍具有亚型依赖性作用，我们将AppNL-G-F和AppNL-F小鼠与E2、E3和E4小鼠杂交。为了区分在任一时间点观察到的基因型差异是否是由于hAPP、hapoE或hAPP × hapoE遗传相互作用的主要影响，我们还对6月龄和18月龄的E2、E3和E4雌性和雄性小鼠进行了行为和认知测试。我们还比较了18个月大的AppNL-G-F和AppNL-F雌性和雄性小鼠在鼠apoE背景下的行为和认知表现，沿着年龄和性别匹配的C57 BL/6 J野生型小鼠。对于两个时间点的许多行为测量，存在APP × APOE相互作用，支持apoE对hAPP/Aβ诱导的行为和认知表现具有亚型依赖性作用。与NL-G-F/E4小鼠相比，NL-G-F/E3小鼠（而非NL-G-F/E2小鼠）的皮质不溶性Aβ42水平较低。NL-F/E3和NL-F/E2小鼠的皮质不溶性Aβ42水平低于NL-F/E4小鼠。这些结果表明，在仅含人APP和apoE的小鼠模型中，对hAPP/Aβ诱导的行为改变和认知障碍以及皮质不溶性Aβ42水平存在apoE亚型依赖性效应。
Mice expressing human amyloid precursor protein (APP) containing the dominant Swedish and Iberian mutations (AppNL–F) or also Arctic mutation (AppNL–G–F) show neuropathology and hippocampus-dependent cognitive impairments pertinent to Alzheimer’s disease (AD) in mouse models at 18 and 6 months of age, respectively. Apolipoprotein E, involved in cholesterol metabolism, plays an important role in maintaining the brain. There are three human apolipoprotein E isoforms: E2, E3, and E4. Compared to E3, E4 increases while E2 protects against AD risk. At 6 months of age, prior to the onset of plaque pathology, E3, but not E4, protected against hAPP/Aβ-induced impairments in spatial memory retention in the Morris water maze. However, these earlier studies were limited as hapoE was not expressed outside the brain and E3 or E4 was not expressed under control of an apoE promotor, E2 was often not included, hAPP was transgenically overexpressed and both mouse and hAPP were present. Therefore, to determine whether apoE has isoform-dependent effects on hAPP/Aβ-induced behavioral alterations and cognitive impairments in adult female and male mice at 6 and 18 months of age, we crossed AppNL–G–F and AppNL–F mice with E2, E3, and E4 mice. To distinguish whether genotype differences seen at either time point were due to main effects of hAPP, hapoE, or hAPP × hapoE genetic interactions, we also behavioral and cognitively tested E2, E3, and E4 female and male mice at 6 and 18 months of age. We also compared behavioral and cognitive performance of 18-month-old AppNL–G–F and AppNL–F female and male mice on a murine apoE background along with that of age—and sex-matched C57BL/6J wild-type mice. For many behavioral measures at both time points there were APP × APOE interactions, supporting that apoE has isoform-dependent effects on hAPP/Aβ-induced behavioral and cognitive performance. NL-G-F/E3, but not NL-G-F/E2, mice had lower cortical insoluble Aβ42 levels than NL-G-F/E4 mice. NL-F/E3 and NL-F/E2 mice had lower cortical insoluble Aβ42 levels than NL-F/E4 mice. These results demonstrate that there are apoE isoform-dependent effects on hAPP/Aβ-induced behavioral alterations and cognitive impairments and cortical insoluble Aβ42 levels in mouse models containing only human APP and apoE.
登录
查看更多内容
影响因子：
4.6
作者：
Li, Kaicheng;Luo, Xiao;Zhang, Minming
通讯作者：
Zhang, Minming
影响因子：
7.6
作者：
Johnson, Lance A.;Zuloaga, Damian G.;Raber, Jacob
通讯作者：
Raber, Jacob
影响因子：
6.1
作者：
Fagan, AM;Watson, M;Holtzman, DM
通讯作者：
Holtzman, DM
体重指数轨迹和老年人患阿尔茨海默氏病的风险。
影响因子：
4.6
作者：
Kang SY;Kim YJ;Jang W;Son KY;Park HS;Kim YS
通讯作者：
Kim YS
影响因子：
4.6
作者：
Kundu P;Torres ERS;Stagaman K;Kasschau K;Okhovat M;Holden S;Ward S;Nevonen KA;Davis BA;Saito T;Saido TC;Carbone L;Sharpton TJ;Raber J
通讯作者：
Raber J