The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol
The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol
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DOI：
10.1016/j.neurobiolaging.2007.04.018
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发表时间：
2008-12-01
影响因子：
4.2
通讯作者：
Colton, Carol A.
中科院分区：
文献类型：
--
作者：
Brown, Candice M.;Choi, Emily;Colton, Carol A.
载脂蛋白E4 （APOE4）基因是众所周知的阿尔茨海默病（AD）和其他神经系统疾病的危险因素。表达至少一种APOE4基因的绝经后AD妇女比不表达APOE4基因的妇女有更严重的神经病理和更差的认知评分。由于17 β -雌二醇下调炎症作为其神经保护作用的一部分，我们研究了17 β -雌二醇作为APOE基因型的功能对小胶质细胞免疫激活反应的影响。我们的数据显示，与APOE3小鼠相比，17 β -雌二醇在APOE4靶向替代小鼠中的抗炎活性显著降低。APOE基因型与免疫激活小胶质细胞对17 β -雌二醇的应答之间存在显著的相互作用。基因型特异性效应并不局限于脑巨噬细胞，因为APOE4卵巢切除小鼠的腹腔巨噬细胞在17 β -雌二醇反应方面也表现出显著差异。APOE4小胶质细胞中的ER β蛋白水平高于APOE-3小胶质细胞，提示APOE4基因存在时翻译后蛋白调控存在差异。总的来说，我们的数据表明，APOE基因型可能是评估17 - β -雌二醇作用有效性的关键组成部分，并且可能影响17 - β -雌二醇的神经保护作用和当APOE4基因表达时激素替代疗法对脑功能的影响。(c) 2007爱思唯尔公司版权所有。
The apolipoprotein E4 (APOE4) gene is a well-known risk factor for Alzheimer's disease (AD) and other neurological disorders. Postmenopausal women with AD who express at least one APOE4 gene have more severe neuropathology and worsened cognitive scores than their non-expressing counterparts. Since 17 beta-estradiol down-regulates inflammation as part of its neuroprotective role, we examined the effect of 17 beta-estradiol on the response of microglia to immune activation as a function of APOE genotype. Our data show that the anti-inflammatory activity of 17 beta-estradiol is significantly reduced in APOE4 targeted replacement mice compared to APOE3 mice. A significant interaction between APOE genotype and the response to 17 beta-estradiol was observed for NO and cytokine production by immune activated microglia. The genotype specific effect was not restricted to brain macrophages since peritoneal macrophages from APOE4 ovariectomized mice also demonstrated a significant difference in 17 beta-estradiol responsiveness. ER beta protein levels in APOE4 microglia were higher than APOE-3 microglia, suggesting a difference in post-translational protein regulation in the presence of the APOE4 gene. Overall, our data indicate that the APOE genotype may be a critical component in assessing the effectiveness of 17 beta-estradiol's action and may impact the neuroprotective role of 17 beta-estradiol and of hormone replacement therapy on brain function when the APOE4 gene is expressed. (c) 2007 Elsevier Inc. All rights reserved.