Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation.
Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation.
复制标题
DOI：
10.1186/1742-2094-9-192
复制
发表时间：
2012-08-10
影响因子：
9.3
通讯作者：
Keene CD
中科院分区：
文献类型：
--
作者：
Cudaback E;Li X;Yang Y;Yoo T;Montine KS;Craft S;Montine TJ;Keene CD
人类载脂蛋白（apo） E基因（APOE） ϵ4等位基因的遗传除了对其他神经系统疾病的临床结果产生不利影响外，还会显著增加患阿尔茨海默病（AD）的风险。虽然apoE亚型与淀粉样蛋白β (a β)的相互作用存在差异，但最近的研究主要集中在AD发病机制中的免疫调节以及与不同apoE等位基因遗传相关的先天免疫调节作用机制上。APOE基因型调节包括APOC1在内的近端基因的表达，APOC1编码一种与a β斑块相关的小载脂蛋白。在这里，我们检验了apoe基因型依赖性先天免疫调节可能部分由apoe - 1介导的假设。采用ELISA法测定不同APOE基因型对照者脑脊液中APOE - 1的浓度。采用Real-time PCR和ELISA分别分析APOE在小鼠肝脏、血清、大脑皮层和培养的原代星形胶质细胞中的mRNA和蛋白表达，并将小鼠APOE靶向替代为人APOE ϵ3或ϵ4。利用特异性toll样受体激动剂LPS和PIC以及Aβ，研究了apoc - 1在培养小鼠初级小胶质细胞和星形胶质细胞以及人分化巨噬细胞中对先天免疫活性的直接调节。在人类和APOE靶向替代小鼠中，APOE - 1水平随APOE基因型的不同而变化，ϵ4携带者在两种物种中都显示出显著减少的APOE - 1。apoc - 1在LPS、PIC或Aβ刺激下，能有效降低小鼠小胶质细胞、星形胶质细胞和人巨噬细胞的促炎细胞因子分泌。c - 1具有免疫抑制作用。我们的结果阐明了APOE基因型阿尔茨海默病风险的一种新的潜在机制；其中，ϵ4等位基因患者的apoc - 1表达降低，导致先天免疫活性增加。
Inheritance of the human ϵ4 allele of the apolipoprotein (apo) E gene (APOE) significantly increases the risk of developing Alzheimer’s disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases. While apoE isoforms differentially interact with amyloid β (Aβ), a pleiotropic neurotoxin key to AD etiology, more recent work has focused on immune regulation in AD pathogenesis and on the mechanisms of innate immunomodulatory effects associated with inheritance of different APOE alleles. APOE genotype modulates expression of proximal genes including APOC1, which encodes a small apolipoprotein that is associated with Aβ plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I. ApoC-I concentration in cerebrospinal fluid from control subjects of differing APOE genotypes was quantified by ELISA. Real-time PCR and ELISA were used to analyze apoC-I mRNA and protein expression, respectively, in liver, serum, cerebral cortex, and cultured primary astrocytes derived from mice with targeted replacement of murine APOE for human APOE ϵ3 or ϵ4. ApoC-I direct modulation of innate immune activity was investigated in cultured murine primary microglia and astrocytes, as well as human differentiated macrophages, using specific toll-like receptor agonists LPS and PIC as well as Aβ. ApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with ϵ4 carriers showing significantly less apoC-I in both species. ApoC-I potently reduced pro-inflammatory cytokine secretion from primary murine microglia and astrocytes, and human macrophages, stimulated with LPS, PIC, or Aβ. ApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an ϵ4 allele have decreased expression of apoC-I resulting in increased innate immune activity.
登录
查看更多内容
APOE 位点遗传变异的功能分析表明区域增强子参与 TOMM40 和 APOE 的调节。
影响因子：
3.5
作者：
通讯作者：
--
影响因子：
168.9
作者：
Ballard, Clive;Gauthier, Serge;Jones, Emma
通讯作者：
Jones, Emma
影响因子：
6.5
作者：
Abildayeva, Karlygash;Berbee, Jimmy F. P.;Mulder, Monique
通讯作者：
Mulder, Monique
影响因子：
4.4
作者：
Chen, Hsuan Pu;Lin, Andy;Smith, Desmond J.
通讯作者：
Smith, Desmond J.
影响因子：
6.5
作者：
Berbee, Jimmy F. P.;Coomans, Claudia P.;Rensen, Patrick C. N.
通讯作者：
Rensen, Patrick C. N.