炎症过程中载脂蛋白E亚型在星形胶质细胞和小胶质细胞的表达和分泌  

Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation

作　　者：Maria Fe Lanfranco Jordy Sepulveda Gregory Kopetsky GWilliam Rebeck 杜一星(编译) Maria Fe Lanfranco;Jordy Sepulveda;Gregory Kopetsky;GWilliam Rebeck(Department of Neuroscience,Georgetown University Medical Center,Washington,District of Columbia,USA;Department of Pharmacology&Physiology,Georgetown University Medical Center,Washington,District of Columb ia,USA.)

机构地区：[1]Department of Neuroscience,Georgetown University Medical Center,Washington,District of Columbia,USA [2]Department of Pharmacology&Physiology,Georgetown University Medical Center,Washington,District of Columb ia,USA. [3]不详

出　　处：《神经损伤与功能重建》2021年第6期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：神经炎症是神经退行性疾病的常见特征,受阿尔茨海默病危险因素载脂蛋白E(APOE)的调节。apoE蛋白在大脑中由星形胶质细胞和小胶质细胞合成。在人类APOE(E2、E3和E4)靶向替代小鼠的星形胶质细胞和小胶质细胞的原代培养物中,我们发现星形胶质细胞分泌2种apoE,而细胞内apoE只包含1种。2种形式的分泌型星形胶质细胞apoE在糖蛋白分离过程中均发生结合,酶促去除聚糖使2种形式的apoE融合为单一形式。因此,星形胶质细胞分泌的2种apoE是不同的糖基化的蛋白。小胶质细胞仅释放1种apoE,而细胞内apoE则由2种形式组成;分泌的apoE和2种细胞内apoE中的其中1种是糖基化的。我们用内源性肿瘤坏死因子α(TNFα)或外源性脂多糖(LPS)促炎刺激物处理原代培养的胶质细胞。LPS对星形细胞的apoE没有影响,而APOE2和APOE3小胶质细胞释放的apoE增加;对APOE4小胶质细胞也没有影响。与APOE2和APOE3小胶质细胞相比,APOE4小胶质细胞显示出更高的TNFα基线分泌。TNFα处理仅降低了APOE4星形胶质细胞中apoE的分泌和细胞表达。星形胶质细胞和小胶质细胞产生apoE种类的模式不受炎症的影响。2种处理后的星形胶质细胞中均未显示APOE mRNA的变化。总之,我们的数据表明,星形胶质细胞和小胶质细胞差异表达和分泌糖基化形式的apoE;并且相较于APOE2和APOE3,APOE4星形胶质细胞和小胶质细胞在免疫调节方面存在缺陷。Neuroinflammation is a common feature in neurodegenerative diseases,modulated by the Alzheimer’s dis-ease risk factor,apolipoprotein E(APOE).In the brain,apoE protein is synthesized by astrocytes and microglia.We ex-amined primary cultures of astrocytes and microglia from human APOE(E2,E3,and E4)targeted-replacement mice.Astrocytes secreted two species of apoE,whereas cellular apoE consisted of only one.Both forms of secreted astrocytic apoE were bound during glycoprotein isolation,and enzymatic removal of glycans produced a convergence of the two forms of apoE to a single form;thus,the two species of astrocyte-secreted apoE are differentially glycosylated.Microg-lia released only a single species of apoE,while cellular apoE consisted of two forms;the secreted apoE and one of the two forms of cellular apoE were glycosylated.We treated the primary glia with either endogenous(TNFα)or exogenous(LPS)pro-inflammatory stimuli.While LPS had no effect on astrocytic apoE,APOE2,and APOE3 microglia increased release of apoE;APOE4 microglia showed no effect.APOE4 microglia showed higher baseline secretion of TNFαcom-pared to APOE2 and APOE3 microglia.TNFαtreatment reduced the secretion and cellular expression of apoE only in APOE4 astrocytes.The patterns of apoE species produced by astrocytes and microglia were not affected by inflamma-tion.No changes in APOE mRNA were observed in astrocytes after both treatments.Together,our data demonstrate that astrocytes and microglia differentially express and secrete glycosylated forms of apoE and that APOE4 astrocytes and microglia are deficient in immunomodulation compared to APOE2 and APOE3.

关 键 词：阿尔茨海默病 载脂蛋白E 胶质细胞 炎症 翻译后修饰 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]