ApoE 4 reduces the expression of Aβ degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons

被引：32

作者：

Du, Jing ^{[1
]}

Chang, Junlei ^{[1
]}

Guo, Songxi ^{[1
]}

Zhang, Qing ^{[1
]}

Wang, Zhao ^{[1
]}

机构：

[1] Tsinghua Univ, Sch Med, Dept Biol Sci & Biotechnol, Prot Sci Key Lab,Minist Educ, Beijing 100084, Peoples R China

来源：

NEUROSCIENCE LETTERS | 2009年 / 464卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Alzheimer's disease; ApoE4; Insulin-degrading enzyme; NMDA receptor; PKA; ONSET ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; THERAPEUTIC TARGET; TRANSGENIC MICE; E4; PROTEIN; CELLS; CALCIUM; INSULIN; BINDING;

D O I：

10.1016/j.neulet.2009.07.032

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Apolipoprotein E (ApoE) 4 is a potent risk factor for Alzheimer's disease (AD). However, the mechanism underlying ApoE4 function in the pathology of AD is not well understood. We report here that, in comparison with ApoE2 and ApoE3, ApoE4 significantly reduces levels of insulin-degrading enzyme (IDE), which is responsible for the cellular clearance of A beta in neurons. This differential regulation of IDE by various ApoE isoforms was blocked by coincubation with N-methyl-D-aspartic acid (NMDA) receptor inhibitors and receptor-associated protein (RAP), which blocked the interaction between ApoE and members of the low-density lipoprotein (LDL) receptor family. Moreover, inhibition of the NMDA receptor increased IDE levels in neurons, while activation of the NMDA receptor-reduced IDE expression. Further studies demonstrate that, as a pathway downstream of the NMDA receptor, CAMP-dependent protein kinase (PKA) contributes to the NMDA receptor-reduced IDE expression. These results suggest that ApoE4 down-regulates IDE expression in neurons by binding to its receptor and stimulating the NMDA receptor pathway, which may account for its role in AD pathogenesis. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

引用

页码：140 / 145

页数：6

共 22 条

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STABLE EXPRESSION AND SECRETION OF APOLIPOPROTEINS E3 AND E4 IN MOUSE NEUROBLASTOMA-CELLS PRODUCES DIFFERENTIAL-EFFECTS ON NEURITE OUTGROWTH [J].