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

使用纯合的人载脂蛋白E2（APOE2）（2/2） - ，APOE3（3/3） - 或APOE4（4/4）-Knock-In（Ki-ki）小鼠，进行了演讲研究，以检查以下四个方面：（I）对早期的Infrarct ISCH ISCH ISCH ISCH ISCH ISCH ISCH ISCH ISCH ISCH ISCH的比较。（iii）比较局灶性脑缺血后的APOE同工型特异性在发生延迟梗塞扩张的情况下的比较；（iii）对APOE4同工型特异性脑损伤加重的可能机制的分析；（iv）该病理学的可能的治疗干预措施。在2002年，在4/4-KI小鼠中发现梗塞体积和神经系统的定义明显比2/2-和3/3 ki小鼠在局灶性脑缺血后24小时比在2/2-和3/3-ki小鼠中差，这表明apoe4 exefient in Inferion in Infertion in Infertion in Infertion retantion retantion in Infctien retaniguts in Infartion.eftrar in Infctien in Infarcien retancien retanigiation。在亚急性期（1至7天）的局灶性大脑期间的星形细胞激活是……以同种异体特异性的方式（APOE4> apoE3 = apoE2）在4/4 KI小鼠中显着加重了化学药。上述数据表明，APOE4同工型起作用增强反应性星形胶质细胞增多症和相关的炎症反应，从而加剧了延迟的梗塞扩张。在2004年和2005年，进行了本研究，以探测预测的催化性催化剂关系，以探测增强的星形胶质激活和在4/4-ki MiM损害中的增强脑损伤之间的催化关系，（R） - （ - ） - 2-丙氯辛酸（通过S-100蛋白质合成的负调控来抑制星形胶质细胞活化）。此外，本研究的目的是扩展剂对APOE4同工型特异性脑损伤的可能临床应用。结果清楚地表明，在4/4-KI小鼠中，arundicac诱导的侵袭周围区域中S100/GFAP免疫反应性燃烧的衰减远大于2/2或3/3-KI小鼠中的S100/GFAP免疫反应性燃烧。与Ki小鼠的其他两种遗传系相比，通过在射周围场区域中明显的星形胶质性激活（通过S100B/GFAP免疫反应性Burnen的增加）来实现4/4-KI小鼠延迟梗塞扩张的加剧。以上结果表明，APOE4同工型通过增强星形胶质细胞激活而加剧了大脑缺血的亚急性阶段的脑损伤。基于在过去四年（2002年至2005年）在连续研究中获得的上述数据（2002年至2005年），本研究证明了APOE4等级exAcecormormemorm specection saccation saccation saccation sakebation saveific actection; （ii）在这种现象的发病机理中，星形细胞激活增强与脑损伤加剧之间的因果关系；（iii）通过药物对APOE4同工型特异性神经元脆弱性的星形细胞激活的药物调节，一种新型的治疗策略。较少的