Apolipoprotein E isoform-dependent microglia migration
Apolipoprotein E isoform-dependent microglia migration
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DOI：
10.1096/fj.10-176891
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发表时间：
2011-06-01
期刊：
影响因子：
4.8
通讯作者：
Keene, C. Dirk
中科院分区：
文献类型：
--
作者：
Cudaback, Eiron;Li, Xianwu;Keene, C. Dirk
补体成分C5 a和ATP是小胶质细胞运动的有效效应物，并且在各种神经退行性疾病和损伤部位增加。载脂蛋白E（apoE）影响小胶质细胞的功能，不同的人类apoE亚型赋予神经退行性疾病，特别是阿尔茨海默病的发展可变的风险。本研究的目的是检验小鼠apoE和人apoE亚型影响小胶质细胞迁移的假设。使用原始野生型和apoE缺陷型小胶质细胞，我们发现C5 a和ATP刺激的趋化性在很大程度上是apoE依赖的过程与不同的分子基础。虽然野生型小胶质细胞的C5 a依赖性趋化性被受体相关蛋白（RAP）完全阻断，表明apoE受体参与，ATP刺激的迁移不受RAP的影响，但与差异ERK磷酸化有关。使用源自针对APOE的人apoE 2（apoE 2）、apoE 3（apoE 3）或apoE 4（apoE 4）等位基因的编码外显子（蛋白质同种型）“人源化”的靶向置换小鼠的原代小胶质细胞的研究显示，与表达人apoE 3的小胶质细胞相比，表达apoE 4或apoE 2的原代小鼠小胶质细胞表现出显著降低的C5 a和ATP刺激的迁移。这项研究首次证明了apoE依赖性和apoE亚型特异性调节小胶质细胞迁移，以响应通常与神经退行性疾病相关的不同趋化刺激。Cudaback，E.，Li，X.，Montine，K.美国，Montine，T. J.，基恩角D.载脂蛋白E亚型依赖性小胶质细胞迁移。FASEB J.25，2082-2091（2011）。www.fasebj.org
Complement component C5a and ATP are potent effectors of microglial movement and are increased in diverse neurodegenerative diseases and at sites of injury. Apolipoprotein E (apoE) influences microglial function, and different human apoE isoforms confer variable risk for development of neurodegenerative disorders, especially Alzheimer's disease. The purpose of this investigation was to test the hypothesis that mouse apoE and human apoE isoforms influence microglial migration. Using primary wild-type and apoE-deficient microglia, we show that C5a- and ATP-stimulated chemotaxis are largely apoE-dependent processes with different molecular bases. Although the C5a-dependent chemotaxis of wild-type microglia was completely blocked by receptor-associated protein (RAP), suggesting apoE receptor involvement, ATP-stimulated migration was unaffected by RAP but was associated with differential ERK phosphorylation. Studies using primary microglia derived from targeted replacement mice "humanized" for the coding exons (protein isoform) of human epsilon 2 (apoE2), epsilon 3 (apoE3), or epsilon 4 (apoE4) allele of APOE revealed that primary mouse microglia expressing apoE4 or apoE2 exhibited significantly reduced C5a- and ATP-stimulated migration compared with microglia expressing human apoE3. This study, for the first time, demonstrates apoE dependence and apoE isoform-specific modulation of microglial migration in response to distinct chemotactic stimuli commonly associated with neurodegenerative disease.-Cudaback, E., Li, X., Montine, K. S., Montine, T. J., Keene, C. D. Apolipoprotein E isoform-dependent microglia migration. FASEB J. 25, 2082-2091 (2011). www.fasebj.org