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Apolipoprotein E isoform-specific effects on lipoprotein receptor processing

机译:载脂蛋白E同工型对脂蛋白受体加工的影响

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摘要

Recent findings indicate an isoform-specific role for apolipoprotein E (apoE) in the elimination of beta-amyloid (Aβ) from the brain. ApoE is closely associated with various lipoprotein receptors, which contribute to Aβ brain removal via metabolic clearance or transit across the blood-brain barrier (BBB). These receptors are subject to ectodomain shedding at the cell surface, which alters endocytic transport and mitigates Aβ elimination. To further understand the manner in which apoE influences Aβ brain clearance, these studies investigated the effect of apoE on lipoprotein receptor shedding. Consistent with prior reports, we observed an increased shedding of the low density lipoprotein receptor (LDLR) and the LDLR-related protein 1 (LRP1) following Aβ exposure in human brain endothelial cells. When Aβ was co-treated with each apoE isoform, there was a reduction in Aβ-induced shedding with apoE2 and apoE3, while lipoprotein receptor shedding in the presence of apoE4 remained elevated. Likewise, intracranial administration of Aβ to apoE targeted replacement mice (expressing the human apoE isoforms) resulted in an isoform-dependent effect on lipoprotein receptor shedding in the brain (apoE4>apoE3>apoE2). Moreover, these results show a strong inverse correlation with our prior work in apoE transgenic mice in which apoE4 animals showed reduced Aβ clearance across the BBB compared to apoE3 animals. Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing Aβ from the brain.
机译:最近的发现表明,载脂蛋白E(apoE)在消除大脑中的β-淀粉样蛋白(Aβ)中具有同工型特异性作用。 ApoE与各种脂蛋白受体密切相关,这些脂蛋白受体通过代谢清除或穿越血脑屏障(BBB)的迁移而有助于Aβ脑的去除。这些受体在细胞表面经受胞外域脱落,这改变了内吞转运并减轻了Aβ的消除。为了进一步了解apoE影响Aβ脑部清除的方式,这些研究调查了apoE对脂蛋白受体脱落的影响。与先前的报道一致,我们观察到人脑内皮细胞暴露于Aβ后,低密度脂蛋白受体(LDLR)和LDLR相关蛋白1(LRP1)的脱落增加。当将Aβ与每种apoE亚型共同处理时,ApoE2和apoE3引起的Aβ诱导的脱落减少,而在apoE4存在的情况下脂蛋白受体脱落仍然升高。同样,向apoE靶向的替代小鼠(表达人apoE亚型)颅内给予Aβ导致对脑中脂蛋白受体脱落的亚型依赖性效应(apoE4> apoE3> apoE2)。此外,这些结果表明与我们先前在apoE转基因小鼠中的研究存在强烈的逆相关性,在该研究中,与apoE3动物相比,apoE4动物在BBB上的Aβ清除率降低。基于这些结果,apoE4在调节脂蛋白受体脱落方面似乎不如其他apoE亚型有效,这可能解释了这些亚型在从大脑中去除Aβ的不同作用。

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