Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice:: Increased susceptibility of females
Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice:: Increased susceptibility of females
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DOI：
10.1073/pnas.95.18.10914
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发表时间：
1998-09-01
影响因子：
11.1
通讯作者：
Mucke, L
中科院分区：
文献类型：
--
作者：
Raber, J;Wong, D;Mucke, L
载脂蛋白E （apoE）介导脂质在细胞间的再分配，在脑和肝脏中表达水平最高。人类载脂蛋白e存在于由不同等位基因编码的三种主要亚型(epsilon(2)、epsilon（3)和epsilon(4)）中。与APOE epsilon(2)和epsilon(3)相比，APOE epsilon(4)增加了认知障碍的风险，降低了阿尔茨海默病（AD）的发病年龄，降低了对AD治疗的反应。除年龄外，APOE ε(4)等位基因的遗传是散发性阿尔茨海默病（AD）最常见的发病形式的已知最重要的危险因素。虽然已经提出了许多假设，但APOE epsilon(4)如何影响认知和增加AD风险仍不清楚。为了评估不同的人类APOE亚型对大脑的影响，我们使用神经元特异性烯醇酶（NSE）启动子在缺乏内源性小鼠APOE的转基因小鼠的神经元中表达相似水平的人类apoE3或apoE4，与NSE-apoE3小鼠和野生型对照相比。NSE-apoE4小鼠在学习水迷宫任务和垂直探索行为方面表现出损伤，这种损伤随着年龄的增长而增加，主要出现在雌性小鼠中。这些发现表明，人类apoE亚型在体内对脑功能有不同的影响，对apoe4诱导的缺陷的易感性受到年龄和性别的严重影响。这些结果可能与人类APOE epsilon(4)携带者观察到的认知障碍有关。NSE-apoE3小鼠和类似模型可以促进apoe相关认知缺陷治疗的临床前评估。
Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon(2), epsilon(3), and epsilon(4)). Compared with APOE epsilon(2) and epsilon(3), APOE epsilon(4) increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon(4) allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon(4) might affect cognition and increase AD risk To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE, Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon(4) carriers. NSE-apoE3 mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits.