The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated β-amyloid protein internalization in mouse brain
The p38 mitogen-activated protein kinase signaling pathway is involved in regulating low-density lipoprotein receptor-related protein 1-mediated β-amyloid protein internalization in mouse brain
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p38 丝裂原激活蛋白激酶信号通路参与调节小鼠大脑中低密度脂蛋白受体相关蛋白 1 介导的 β-淀粉样蛋白内化
DOI：
10.1016/j.biocel.2016.04.019
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发表时间：
2016-07-01
影响因子：
4
通讯作者：
Qu, Qiu-Min
中科院分区：
文献类型：
--
作者：
Ma, Kai-Ge;Lv, Jia;Qu, Qiu-Min
阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病之一。近年来，越来越多的证据表明，细胞内β-淀粉样蛋白（A β）单独在AD的进展中起着关键作用。因此，了解控制A β内化的信号通路和蛋白质可能为调节A β水平提供新的见解。在本研究中，通过低密度脂蛋白受体相关蛋白1（LRP 1）的p38丝裂原活化蛋白激酶（MAPK）的A β内化的调节进行了体内分析。来自该研究的数据显示，A β（1-42）被小鼠脑中的神经元和星形胶质细胞内化，并且主要沉积在线粒体和溶酶体中，其中一些也在内质网中发现。在A β（1 - 42）内化过程中形成β（1 - 42）-LRP 1复合物，并且A β（1-42）通过LRP 1激活p38 MAPK信号通路。A β（1-42）和LRP 1共定位于顶叶皮层和海马的细胞中。此外，LRP 1-mRNA和LRP 1蛋白水平参与了小鼠脑内A β（1-42）的内化。本研究的结果表明，A β（1-42）诱导LRP 1依赖性途径，该途径与p38 MAPK的激活有关，导致A β（1-42）的内化。这些结果为p38 MAPK信号通路在体内通过LRP 1参与调节小鼠顶叶皮层和海马中A β（1-42）内化提供了证据。(C)2016爱思唯尔有限公司版权所有
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Recently, increasing evidence suggests that intracellular beta-amyloid protein (A beta) alone plays a pivotal role in the progression of AD. Therefore, understanding the signaling pathway and proteins that control A beta internalization may provide new insight for regulating A beta levels. In the present study, the regulation of A beta internalization by p38 mitogen-activated protein kinases (MAPK) through low-density lipoprotein receptor-related protein 1 (LRP1) was analyzed in vivo. The data derived from this investigation revealed that A beta(1-42) were internalized by neurons and astrocytes in mouse brain, and were largely deposited in mitochondria and lysosomes, with some also being found in the endoplasmic reticulum. A beta(1-42)-LRP1 complex was formed during A beta(1-42) internalization, and the p38 MAPK signaling pathway was activated by A beta(1-42) via LRP1. A beta(1-42) and LRP1 were co-localized in the cells of parietal cortex and hippocampus. Furthermore, the level of LRP1-mRNA and LRP1 protein involved in A beta(1-42) internalization in mouse brain. The results of this investigation demonstrated that A beta(1-42) induced an LRP1-dependent pathway that related to the activation of p38 MAPK resulting in internalization of A beta(1-42). These results provide evidence supporting a key role for the p38 MAPK signaling pathway which is involved in the regulation of A beta(1-42) internalization in the parietal cortex and hippocampus of mouse through LRP1 in vivo. (C) 2016 Elsevier Ltd. All rights reserved.