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脉络丛上皮细胞β-淀粉样蛋白转运体表达的年龄变化：氧化应激损伤的作用

刘重斌, 王瑞, 董缪武, 高喜仁, 俞峰

湖州师范学院医学院基础医学系生理与药理教研室，湖州 313000；温州医科大学基础医学院生理教研室，温州 325000

摘要

老龄化可引起β-淀粉样蛋白(amyloid β-peptide, Aβ)在脑内的蓄积。Aβ的清除是通过中枢神经系统与外周血液循环的屏障的主动转运过程来实现。本文旨在研究血-脑脊液屏障脉络丛上皮细胞中与Aβ清除转运相关蛋白随年龄增长的表达变化。取不同月龄大鼠，用透射电镜观察脉络丛上皮细胞的形态改变，用实时定量RT-PCR方法检测脉络丛上皮细胞Aβ42、Aβ转运相关蛋白[低密度脂蛋白受体相关蛋白(LRP)-1、LRP-2、P-糖蛋白(P-gp)和糖基化终产物受体蛋白(RAGE)]和氧化应激损伤相关蛋白[血红蛋白氧化酶-1 (HO-1)和caspase-3]的mRNA表达水平。结果显示：(1) 随着年龄的增加，脉络丛上皮细胞形态出现了明显的退化和萎缩；(2) Aβ42的mRNA表达随着年龄的增加而增加，差异具有显著性；(3) Aβ转运相关蛋白LRP-1和P-gp的mRNA表达随着年龄的增加而下降，差异具有显著性；LRP-2的mRNA表达随着年龄的增加而增加，差异具有显著性；RAGE的mRNA表达没有明显变化；(4) 氧化应激损伤相关蛋白HO-1和caspase-3的mRNA表达随着年龄的增加而增加，差异具有显著性。以上结果表明，随着年龄的增加，脉络丛上皮组织中的Aβ清除相关蛋白表达下降，清除能力下降，引起Aβ蓄积，继而导致氧化应激损伤，引起脉络丛上皮退化和萎缩，加重Aβ在脑内的毒性，加快炎症反应和神经退行性变化的进程。

关键词： 老化; β-淀粉样蛋白; 脉络丛; 血-脑脊液屏障; 低密度脂蛋白受体相关蛋白; P-糖蛋白; 糖基化终产物受体蛋白

Amyloid-beta transporter expression at the choroid plexus in normal aging: the possibility of reduced resistance to oxidative stress insults

LIU Chong-Bin, WANG Rui, DONG Miao-Wu, GAO Xi-Ren, YU Feng

Department of Physiology, School of Medicine, Huzhou Normal College, Huzhou 313000, China； Department of Physiology, Wenzhou Medical University, Wenzhou 325000, China

Abstract

Accumulation of amyloid-beta peptides (Aβ) results in amyloid burden in normal aging brain. Clearance of this peptide from the brain occurs via active transport at the interfaces separating the central nervous system (CNS) from the peripheral circulation. The present study was to investigate the change of Aβ transporters expression at the choroid plexus (CP) in normal aging. Morphological modifications of CP were observed by transmission electron microscope. Real-time RT-PCR was used to measure mRNA expressions of Aβ₄₂ and its transporters, which include low density lipoprotein receptor-related protein-1 and 2 (LRP-1 and -2), P-glycoprotein (P-gp) and the receptor for advanced glycation end-products (RAGE), at the CP epithelium in rats at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months. At the same time, the mRNA expressions of oxidative stress-related proteins were also measured. The results showed that a striking deterioration of the CP epithelial cells and increased Aβ₄₂ mRNA expression were observed in aged rats, and there was a decrease in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE mRNA expression and an increase in LRP-2, the CP epithelium Aβ influx transporter. Heme oxygenase-1 (HO-1) and caspase-3 expressions at the CP epithelium increased with age at the mRNA level. These results suggest the efficacy of the CP in clearing of Aβ deceases in normal aging, which results in the increase of brain Aβ accumulation. And excess Aβ interferes with oxidative phosphorylation, leads to oxidative stress and morphological structural changes. This in turn induces further pathological cascades of toxicity, inflammation and neurodegeneration process.

Key words: aging; amyloid-beta; choroid plexus; blood-CSF-barrier; low density lipoprotein receptor-related protein; P-glycoprotein; receptor for advanced glycation end-products

收稿日期：2013-07-27　　录用日期：2013-09-11

通讯作者：刘重斌　　E-mail: liuchongbin1972@126.com

引用本文：

刘重斌, 王瑞, 董缪武, 高喜仁, 俞峰. 脉络丛上皮细胞β-淀粉样蛋白转运体表达的年龄变化：氧化应激损伤的作用[J]. 生理学报 2014; 66 (2): 158-168.

LIU Chong-Bin, WANG Rui, DONG Miao-Wu, GAO Xi-Ren, YU Feng. Amyloid-beta transporter expression at the choroid plexus in normal aging: the possibility of reduced resistance to oxidative stress insults. Acta Physiol Sin 2014; 66 (2): 158-168 (in Chinese with English abstract).