Duan Rui-Sheng, Chen Zhiguo, Dou Ying-Chun, Concha Quezada Hernan, Nennesmo Inger, Adem Abdu, Winblad Bengt, Zhu Jie
Division of Experimental Geriatrics (Novum, plan 5), Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
Exp Neurol. 2006 Dec;202(2):373-80. doi: 10.1016/j.expneurol.2006.06.013. Epub 2006 Aug 17.
Apolipoprotein E (apoE) down-regulates microglial activation and the secretion of inflammatory molecules in an isoform specific fashion (E2 > E3 > E4); the E4 isoform is over-represented in Alzheimer cases while E2 is under-represented. To better define the role of apoE in neurodegeneration, we contrasted apoE knockout (n = 38) and wild-type mice (n = 41) with respect to seizure activity, mortality, locomotion, hippocampal microglial activation/chemokine receptor expression, and damage to the hippocampus after nasal administration of kainic acid (KA) (water as controls). Mice lacking apoE demonstrated more hunching and less rearing, more damage to neurons in the CA3 region (mean histopathologic score: 3.7 vs. 1.6, p < 0.05), greater microglial activation confirmed by high levels of CD11b and CD86 expression in hippocampus (CD11b p < 0.01, CD86 p < 0.05), and a greater percentage of activated microglia expressing CC chemokine receptors 3 (CCR3) (p < 0.05). Taken together, these findings imply that apoE modulates hippocampal damage induced by KA and found early in the sequence of human Alzheimer's brain changes, by modulating microglial activation.
载脂蛋白E（apoE）以异构体特异性方式（E2>E3>E4）下调小胶质细胞活化和炎症分子分泌；在阿尔茨海默病病例中，E4异构体比例过高，而E2比例过低。为了更好地确定apoE在神经退行性变中的作用，我们比较了apoE基因敲除小鼠（n = 38）和野生型小鼠（n = 41）在癫痫发作活动、死亡率、运动能力、海马小胶质细胞活化/趋化因子受体表达以及经鼻腔给予海藻酸（KA）（以水作为对照）后海马损伤方面的差异。缺乏apoE的小鼠表现出更多弓背和更少竖毛行为，CA3区神经元损伤更严重（平均组织病理学评分：3.7对1.6，p<0.05），海马中高水平的CD11b和CD86表达证实小胶质细胞活化程度更高（CD11b p<0.01，CD86 p<0.05），且表达CC趋化因子受体3（CCR3）的活化小胶质细胞百分比更高（p<0.05）。综上所述，这些发现表明apoE通过调节小胶质细胞活化来调节KA诱导的海马损伤，而这种损伤在人类阿尔茨海默病脑病变序列中早期就会出现。
