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首页> 外文期刊>Neuroscience Letters: An International Multidisciplinary Journal Devoted to the Rapid Publication of Basic Research in the Brain Sciences >ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons.
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ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons.

机译：ApoE 4通过激活海马神经元中的NMDA受体来降低Abeta降解酶IDE的表达。

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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 Abeta 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.
机译：载脂蛋白E（ApoE）4是阿尔茨海默氏病（AD）的潜在危险因素。但是，AD病理学中的ApoE4功能的基本机制尚不清楚。我们在这里报告，与ApoE2和ApoE3相比，ApoE4显着降低了胰岛素降解酶（IDE）的水平，该酶负责神经元中Abeta的细胞清除。与N-甲基-d-天冬氨酸（NMDA）受体抑制剂和受体相关蛋白（RAP）共同孵育可阻止多种ApoE亚型对IDE的差异调节，从而阻止ApoE与低密度脂蛋白成员之间的相互作用（LDL）受体家族。此外，对NMDA受体的抑制增加了神经元中的IDE水平，而对NMDA受体的激活则降低了IDE表达。进一步的研究表明，cAMP依赖性蛋白激酶（PKA）作为NMDA受体的下游途径，有助于NMDA受体的IDE表达降低。这些结果表明，ApoE4通过与其受体结合并刺激NMDA受体途径来下调神经元中IDE的表达，这可能解释了其在AD发病机理中的作用。

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