A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma
A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma
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DOI：
10.1074/jbc.m112.370130
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发表时间：
2012-07-20
影响因子：
4.8
通讯作者：
Tanihara, Hidenobu
中科院分区：
文献类型：
--
作者：
Hayashi, Hideki;Eguchi, Yuko;Tanihara, Hidenobu
青光眼是一种视神经病变，是仅次于白内障的全球第二大致盲原因。防止视网膜神经节细胞（RGC）丧失是青光眼的主要特征之一，这将是治疗这种疾病的直接方法。然而，到目前为止，神经保护的临床应用并不成功。在这里，我们报告了载脂蛋白e -脂蛋白（E-LPs）保护原代培养的RGCs免受谷氨酸诱导的Ca2+依赖性和线粒体介导的凋亡。E-LPs与低密度脂蛋白受体相关蛋白1结合，募集n -甲基- d -天冬氨酸受体，阻断细胞内Ca2+升高，使糖原合成酶激酶3 β失活，从而抑制细胞凋亡。与用磷酸盐缓冲盐水治疗的对侧眼睛相比，玻璃体内给药E-LPs可以防止谷氨酸转运蛋白缺乏小鼠的RGC丢失，谷氨酸转运蛋白缺乏小鼠是一种正常张力性青光眼模型，会导致青光眼视神经病变，而眼压不会升高。尽管α 2巨球蛋白（低密度脂蛋白受体相关蛋白1的另一种配体）的存在干扰了E-LPs对谷氨酸诱导的神经毒性的神经保护作用，但E-LPs的加入克服了α 2巨球蛋白的抑制作用。这些发现可能为通过lrp1介导的途径治疗正常张力性青光眼提供潜在的治疗策略。
Glaucoma is an optic neuropathy and the second major cause of blindness worldwide next to cataracts. The protection from retinal ganglion cell (RGC) loss, one of the main characteristics of glaucoma, would be a straightforward treatment for this disorder. However, the clinical application of neuroprotection has not, so far, been successful. Here, we report that apolipoprotein E-containing lipoproteins (E-LPs) protect primary cultured RGCs from Ca2+-dependent, and mitochondrion-mediated, apoptosis induced by glutamate. Binding of E-LPs to the low density lipoprotein receptor-related protein 1 recruited the N-methyl-D-aspartate receptor, blocked intracellular Ca2+ elevation, and inactivated glycogen synthase kinase 3 beta, thereby inhibiting apoptosis. When compared with contralateral eyes treated with phosphate-buffered saline, intravitreal administration of E-LPs protected against RGC loss in glutamate aspartate transporter-deficient mice, a model of normal tension glaucoma that causes glaucomatous optic neuropathy without elevation of intraocular pressure. Although the presence of alpha 2-macroglobulin, another ligand of the low density lipoprotein receptor-related protein 1, interfered with the neuroprotective effect of E-LPs against glutamate-induced neurotoxicity, the addition of E-LPs overcame the inhibitory effect of alpha 2-macroglobulin. These findings may provide a potential therapeutic strategy for normal tension glaucoma by an LRP1-mediated pathway.