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Comparison of apolipoprotein E isoform-specific effects after experimental cerebral ischemia.

实验性脑缺血后载脂蛋白E亚型特异性效应的比较。

基本信息

批准号：
14571329
负责人：
MORI Takashi
金额：
$ 2.5万
依托单位：
Saitama Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571329/
关键词：
Apolipoprotein E Acute subacute cerebral ischemia Knock-in mouse Isoform specific Astrocyte 急性期脳虚血

项目摘要

Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, the present study was undertaken to examine the following four aspects : (i)comparison of the apoE isoform specificity on the occurrence of early infarct expansion after focal cerebral ischemia ; (ii)comparison of the apoE isoform specificity on the occurrence of delayed infarct expansion after focal cerebral ischemia ; (iii)the analysis on the possible mechanisms underlying the apoE4 isoform-specific exacerbation of brain damage ; and (iv)the possible therapeutic intervention for this pathology.In 2002, infarct volume and neurologic deficits were found to be significantly worse in 4/4-KI mice than in 2/2- and 3/3-KI mice at 24 hours after focal cerebral ischemia, indicating that the apoE4 isoform exacerbates acute infarct expansion.In 2003, the results demonstrated that delayed infarct expansion and astrocytic activation during the subacute phase (1 to 7 days) of focal cerebral is … More chemia were markedly exacerbated in 4/4-KI mice in an isoform-specific fashion (apoE4>apoE3=apoE2). The above data indicated that the apoE4 isoform acts to augment reactive astrocytosis and the associated inflammatory responses, leading to exacerbation of delayed infarct expansion.In 2004 and 2005, the present study was performed to probe the putative causal relationship between enhanced astrocytic activation and exacerbation of brain damage in 4/4-KI mice using a modulating agent of reactive astrocytes, (R)-(-)-2-propyloctanoic acid (suppression of astrocytic activation through the negative regulation of S-100 protein synthesis). In addition, the present study was aimed to extend the possible clinical application of the agent against apoE4 isoform-specific exacerbation of brain damage. The results clearly showed that the beneficial effects of arundic acid were most pronounced in 4/4-KI mice, wherein delayed infarct expansion together with deterioration of neurologic deficits was significantly mitigated. The attenuation of the S100/GFAP immunoreactive burden in the peri-infarct area induced by arundic acid in 4/4-KI mice was much greater than that in 2/2- or 3/3-KI mice. The aggravation of delayed infarct expansion in 4/4-KI mice was accompanied by pronounced astrocytic activation in the peri-infarct area (as evidenced by an increase in the S100B/GFAP immunoreactive burden) as compared with the other two genetic lines of KI mice. The above results indicate that the apoE4 isoform exacerbates brain injury during the subacute phase of focal cerebral ischemia through augmentation of astrocytic activation.Based on the above data obtained from the consecutive studies during the past four years (2002 to 2005), the present study demonstrated (i)experimental evidence of the apoE4 isoform-specific exacerbation of brain damage ; (ii)causal relationship between enhanced astrocytic activation and exacerbation of brain damage in the pathogenesis of this phenomenon ; (iii)a novel therapeutic strategy by pharmacological modulation of astrocytic activation against apoE4 isoform-specific neuronal vulnerability after stroke. Less

本研究采用纯合子人载脂蛋白E2 (apoE2)(2/2)-、apoE3(3/3)-、apoE4（4/4）敲入（KI）小鼠，从以下四个方面进行研究：(1)比较apoE亚型对局灶性脑缺血后早期梗死扩展发生的特异性；（ii）比较apoE亚型特异性对局灶性脑缺血后迟发性梗死扩展的影响；（iii）分析apoE4亚型特异性脑损伤加重的可能机制；（四）对这种病理可能的治疗干预。2002年，在局灶性脑缺血后24小时，4/4-KI小鼠的梗死面积和神经功能缺损明显大于2/2-和3/3-KI小鼠，这表明apoE4亚型加剧了急性梗死扩展。2003年，研究结果表明，在局灶性脑梗死亚急性期（1 ~ 7天），延迟的梗死扩展和星形细胞激活在4/4-KI小鼠中以亚型特异性的方式（apoE4>apoE3=apoE2）明显加重。上述数据表明，apoE4亚型可增强反应性星形细胞增生和相关的炎症反应，导致延迟性梗死扩张加剧。2004年和2005年，本研究利用星形胶质细胞的调节剂(R)-(-)-2-丙基辛酸（通过负调控S-100蛋白合成抑制星形胶质细胞活化），对4/4-KI小鼠星形胶质细胞活化增强与脑损伤加重之间的假定因果关系进行了探讨。此外，本研究旨在扩大该药物治疗apoE4亚型特异性脑损伤加重的可能临床应用。结果清楚地表明，在4/4-KI小鼠中，环己烷酸的有益作用最为明显，其中延迟的梗死扩展和神经功能缺陷的恶化得到显著缓解。4/4-KI小鼠对梗死周围区域S100/GFAP免疫反应负荷的衰减明显大于2/2-和3/3-KI小鼠。与KI小鼠的其他两个遗传系相比，4/4-KI小鼠延迟性梗死扩展的加重伴随着梗死周围区域明显的星形细胞激活（S100B/GFAP免疫反应负荷增加）。上述结果表明，apoE4亚型通过增强星形细胞激活，在局灶性脑缺血亚急性期加重脑损伤。基于以上在过去四年（2002 - 2005）的连续研究中获得的数据，本研究证明了(1)apoE4亚型特异性脑损伤加重的实验证据；（ii）星形细胞活化增强与脑损伤加剧之间的因果关系；（iii）卒中后通过药理调节星形细胞激活对抗apoE4亚型特异性神经元易感性的新治疗策略。少