Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's disease
Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer's disease
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DOI：
10.1006/nbdi.2002.0483
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发表时间：
2002-04-01
影响因子：
6.1
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Fagan, AM;Watson, M;Holtzman, DM
载脂蛋白E(ApoE)的epsilon 4等位基因是阿尔茨海默病(AD)的危险因素，可能是通过影响淀粉样β蛋白(Abeta)代谢。在表达小鼠apoE、无apoE或人apo2、apoE3或apoE4的老年APP(V717F+/-)小鼠中，对衰老Abeta参数的各种A，3参数的详细分析表明，apoE促进但不是体内Abeta纤维形成所必需的。与小鼠apoE相比，人apoE亚型显著延迟了Abeta的沉积，而apoE 2(和apoE3的程度较小)具有更长的阻止Abeta转化为纤维状的能力。人类载脂蛋白E对Abeta水平和神经性斑块形成的影响与在AD中观察到的相似(E4>；E3>；E2)。重要的是，在Abeta沉积之前，观察到ApoE依赖的可溶性Abeta百分比的降低和膜微区中Abeta的丰富，表明apoE在淀粉样蛋白形成过程的早期影响Abeta的代谢，并提供了apoE影响AD发病的可能的新机制。(C)2002年埃尔塞维尔科学公司(美国)。
The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-beta (Abeta) metabolism. Detailed analyses of various A,3 parameters in aging Abeta parameters in aging APP(V717F+/-) mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Abeta fibril formation in vivo. Human apoE isoforms markedly delayed Abeta deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Abeta from converting into fibrillar forms. Isoform-specific effects of human apoE on Abeta levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Abeta and enrichment of Abeta in membrane microdomains prior to Abeta deposition indicates that apoE influences Abeta metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis. (C) 2002 Elsevier Science (USA).