Kheirandish Leila, Row Barry W, Li Richard C, Brittian Kenneth R, Gozal David
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, KY 40202, USA.
Sleep. 2005 Nov;28(11):1412-7. doi: 10.1093/sleep/28.11.1412.
Exposure to intermittent hypoxia, such as occurs in sleep-disordered breathing, is associated with oxidative stress, cognitive impairments, and increased neuronal apoptosis in brain regions involved in learning and memory. Apolipoprotein E (ApoE) has been implicated in neurodegenerative disorders, and in vitro studies suggest that one of the functions of ApoE may be to confer protection from oxidant stress-induced neuronal cell loss. Therefore, we hypothesized that ApoE-deficient (ApoE-/-) mice would display increased cognitive impairments following intermittent hypoxia. Twenty-four young adult male mice (ApoE-/-) and 24 wild-type littermates (ApoE +/+) were exposed to 14 days of normoxia (room air; n=12 per group) or intermittent hypoxia (5.7% O2 alternating with 21% O2 every 90 seconds, 12 daylight hours per day; n=12 per group). Behavioral testing consisting of a standard place-training reference memory task in the water maze revealed that ApoE+/+ and ApoE-/- mice exposed to intermittent hypoxia were found to require significantly longer times (latency) and distances (pathlength) to locate the hidden platform (P < .005), compared to mice exposed to room air. However, only intermittent hypoxia-exposed ApoE-/- mice were impaired on the final two days of training (P < .03), as well as on measures of spatial bias conducted 24 hours after completion of training (P < .02). Furthermore, increased prostaglandin E2 and malondiadehyde concentrations were present in hippocampal brain tissues following intermittent hypoxia but were significantly higher in ApoE-/- mice (P < .01). Thus, decreased ApoE function is associated with increased susceptibility to neurocognitive dysfunction in a rodent model of sleep-disordered breathing and may underlie the increased prevalence of Apolipoprotein E4 in patients with sleep-disordered breathing.
暴露于间歇性缺氧环境（如睡眠呼吸紊乱时所发生的情况）与氧化应激、认知障碍以及参与学习和记忆的脑区神经元凋亡增加有关。载脂蛋白E（ApoE）与神经退行性疾病有关，体外研究表明ApoE的功能之一可能是保护神经元免受氧化应激诱导的细胞损失。因此，我们推测载脂蛋白E缺陷（ApoE-/-）小鼠在间歇性缺氧后会表现出更严重的认知障碍。将24只成年雄性小鼠（ApoE-/-）和24只同窝野生型小鼠（ApoE+/+）暴露于14天的常氧环境（室内空气；每组n = 12）或间歇性缺氧环境（5.7%氧气与21%氧气每90秒交替一次，每天光照12小时；每组n = 12）。通过水迷宫中的标准位置训练参考记忆任务进行行为测试，结果显示，与暴露于室内空气的小鼠相比，暴露于间歇性缺氧环境的ApoE+/+和ApoE-/-小鼠找到隐藏平台所需的时间（潜伏期）和距离（路径长度）显著更长（P < 0.005）。然而，只有暴露于间歇性缺氧环境的ApoE-/-小鼠在训练的最后两天出现障碍（P < 0.03），以及在训练完成24小时后进行的空间偏差测量中出现障碍（P < 0.02）。此外，间歇性缺氧后海马脑组织中前列腺素E2和丙二醛浓度升高，但ApoE-/-小鼠中的浓度显著更高（P < 0.01）。因此，在睡眠呼吸紊乱的啮齿动物模型中，ApoE功能降低与神经认知功能障碍易感性增加有关，这可能是睡眠呼吸紊乱患者中载脂蛋白E4患病率增加的原因。
