Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease
Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease
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DOI：
10.1016/s0306-4522(00)00069-5
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发表时间：
2000-01-01
期刊：
影响因子：
3.3
通讯作者：
Mucke, L
中科院分区：
文献类型：
--
作者：
Buttini, M;Akeefe, H;Mucke, L
载脂蛋白 E 在脂质转运和损伤后神经组织修复中发挥基本功能。(6,8) 其三种最常见的亚型（E2、E3 和 E4）是多种人类疾病的关键决定因素，包括主要心血管疾病和神经退行性疾病。(8,14) 载脂蛋白 E4 与阿尔茨海默病风险增加 (3,5) 以及头部受伤或中风后临床结果不佳有关。(11,16) 载脂蛋白的确切作用这些条件下的 E4 仍然未知。为了表征人载脂蛋白 E 亚型在体内的作用，我们分析了在大脑中表达载脂蛋白 E3 或 E4 或两者的转基因 Apoe 基因敲除小鼠。半合子和纯合子载脂蛋白 E3 小鼠能够免受年龄相关性和兴奋性毒素诱导的神经变性的影响，而载脂蛋白 E4 小鼠则不然。载脂蛋白E3/E4双基因小鼠与载脂蛋白E4单转基因小鼠一样易受神经变性的影响。八个月大时，纯合子小鼠的神经变性比半合子载脂蛋白 E4 小鼠更严重，这与剂量效应一致。因此，载脂蛋白E4的神经保护作用不仅不如载脂蛋白E3，而且还充当干扰载脂蛋白E3有益功能的显性负因子。抑制载脂蛋白E4的活性可能对于预防和治疗APOE E4携带者的神经变性至关重要。 (C) 2000 IBRO，爱思唯尔科学有限公司出版。
Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and nenrodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimer's disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human alpolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3, The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE E4 carriers. (C) 2000 IBRO, Published by Elsevier Science Ltd.