Villasana Laura E, Akinyeke Tunde, Weber Sydney, Raber Jacob
Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, USA.
Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, USA.
Oncotarget. 2017 Sep 1;8(44):76587-76605. doi: 10.18632/oncotarget.20603. eCollection 2017 Sep 29.
In humans, apoE, which plays a role in repair, is expressed in three isoforms: E2, E3, and E4. E4 is a risk factor for age-related cognitive decline (ACD) and Alzheimer's disease (AD), particularly in women. In contrast, E2 is a protective factor for ACD and AD. E2 and E4 might also differ in their response to cranial Cs irradiation, a form of radiation typically used in a clinical setting for the treatment of cancer. This might be mediated by reactive oxygen species (ROS) in an-apoE isoform-dependent fashion. E2 and E4 female mice received sham-irradiation or cranial irradiation at 8 weeks of age and a standard mouse chow or a diet supplemented with the antioxidant alpha-lipoic acid (ALA) starting at 6 weeks of age. Behavioral and cognitive performance of the mice were assessed 12 weeks later. Subsequently, the generation of ROS in hippocampal slices was analyzed. Compared to sham-irradiated E4 mice, irradiated E4 mice showed enhanced spatial memory in the water maze. This was associated with increased hippocampal PMA-induction of ROS. Similar effects were not seen in E2 mice. Irradiation increased endogenous hippocampal ROS levels in E2 mice while decreasing those in E4 mice. NADPH activity and MnSOD levels were higher in sham-irradiated E2 than E4 mice. Irradiation increased NADPH activity and MnSOD levels in hemi brains of E4 mice but not in those of E2 mice. ALA did not affect behavioral and cognitive performance or hippocampal formation of ROS in either genotype. Thus, apoE isoforms modulate the radiation response.
在人类中，参与修复的载脂蛋白E（apoE）以三种异构体形式表达：E2、E3和E4。E4是与年龄相关的认知衰退（ACD）和阿尔茨海默病（AD）的危险因素，在女性中尤为如此。相比之下，E2是ACD和AD的保护因素。E2和E4对颅脑Cs照射（一种通常用于临床治疗癌症的辐射形式）的反应也可能不同。这可能以依赖载脂蛋白E异构体的方式由活性氧（ROS）介导。E2和E4雌性小鼠在8周龄时接受假照射或颅脑照射，并从6周龄开始给予标准小鼠饲料或补充抗氧化剂α-硫辛酸（ALA）的饲料。12周后评估小鼠的行为和认知表现。随后，分析海马切片中ROS的产生。与假照射的E4小鼠相比，照射后的E4小鼠在水迷宫中的空间记忆增强。这与海马中PMA诱导的ROS增加有关。在E2小鼠中未观察到类似效果。照射增加了E2小鼠海马内源性ROS水平，而降低了E4小鼠的ROS水平。假照射的E2小鼠中NADPH活性和MnSOD水平高于E4小鼠。照射增加了E4小鼠半脑中的NADPH活性和MnSOD水平，但在E2小鼠中未增加。ALA对两种基因型小鼠的行为和认知表现或海马中ROS的形成均无影响。因此，载脂蛋白E异构体调节辐射反应。
