Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels
Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels
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DOI：
10.1074/jbc.m111.295451
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发表时间：
2012-01-13
影响因子：
4.8
通讯作者：
Landreth, Gary E.
中科院分区：
文献类型：
--
作者：
Lee, C. Y. Daniel;Tse, Wayne;Landreth, Gary E.
载脂蛋白 E (APOE) 基因的等位基因变异是散发性阿尔茨海默病的主要危险因素。 ApoE 是大脑中主要的胆固醇载体。此前，我们证明，在 apoE 存在的情况下，小胶质细胞对 β-淀粉样蛋白 (Aβ) 肽的细胞内降解显着增强。然而，促进这种作用的分子机制仍然未知。这项研究报告了 apoE 调节的胆固醇稳态和 Aβ 降解之间的机制联系。我们证明，小胶质细胞促进细胞内 Aβ 降解是 HDL 载脂蛋白（包括 apoE 和 apoA-I）的共同特征。该效应不依赖于 apoE 和 A beta 的直接相互作用。 Aβ 降解的调节是通过单独操纵细胞胆固醇水平来实现的。然而，Aβ降解酶的表达和活性不受胆固醇调节。我们观察到，通过 apoE 降低细胞胆固醇水平会导致 Aβ 更快地递送至溶酶体并增强降解。此外，apoE 促进 Rab7 的回收，Rab7 是一种小型 GTP 酶，负责将运动复合体招募到晚期内体/溶酶体。这些数据表明，在 apoE 存在的情况下，含有 Aβ 的囊泡更快的内吞运输是由于 Rab7 从溶酶体到早期内体的有效回收所致。因此，apoE诱导的细胞内Aβ降解是由apoE的胆固醇流出功能介导的，这降低了细胞胆固醇水平，随后促进Aβ在细胞内运输至溶酶体进行降解。这些发现证明了胆固醇在细胞内 Aβ 降解中的直接作用。
Allelic variation in the apolipoprotein E (APOE) gene is the major risk factor of sporadic Alzheimer disease. ApoE is the primary cholesterol carrier in the brain. Previously, we demonstrated that intracellular degradation of beta-amyloid (A beta) peptides by microglia is dramatically enhanced in the presence of apoE. However, the molecular mechanisms subserving this effect remain unknown. This study reports a mechanistic link between apoE-regulated cholesterol homeostasis and A beta degradation. We demonstrate that promoting intracellular A beta degradation by microglia is a common feature of HDL apolipoproteins, including apoE and apoA-I. This effect was not dependent on the direct interaction of apoE and A beta. Regulation of A beta degradation was achieved by solely manipulating cellular cholesterol levels. The expression and the activity of A beta degrading enzymes, however, were not regulated by cholesterol. We observed that reducing cellular cholesterol levels by apoE resulted in faster delivery of A beta to lysosomes and enhanced degradation. Moreover, apoE facilitated the recycling of Rab7, a small GTPase responsible for recruiting the motor complex to late endosomes/lysosomes. These data indicate that faster endocytic trafficking of A beta-containing vesicles in the presence of apoE resulted from efficient recycling of Rab7 from lysosomes to early endosomes. Thus, apoE-induced intracellular A beta degradation is mediated by the cholesterol efflux function of apoE, which lowers cellular cholesterol levels and subsequently facilitates the intracellular-trafficking of A beta to lysosomes for degradation. These findings demonstrate a direct role of cholesterol in the intracellular A beta degradation.