The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain
The p38 mitogen activated protein kinase regulates β-amyloid protein internalization through the α7 nicotinic acetylcholine receptor in mouse brain
复制标题
p38 丝裂原激活蛋白激酶通过小鼠大脑中的 α7 烟碱乙酰胆碱受体调节 β-淀粉样蛋白内化
DOI：
10.1016/j.brainresbull.2017.11.006
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发表时间：
2018-03-01
影响因子：
3.8
通讯作者：
Qian, Yi-Hua
中科院分区：
文献类型：
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作者：
Ma, Kai-Ge;Lv, Jia;Qian, Yi-Hua
阿尔茨海默病（Alzheimer's disease，AD）是一种严重的神经退行性疾病。细胞内β-淀粉样蛋白（A β）是AD的早期事件。它诱导淀粉样斑块的形成和神经元损伤。α 7烟碱乙酰胆碱受体（α 7 nAChR）已被认为在A β引起的认知中发挥重要作用。它与A β有很高的亲和性，在体外可介导A β的内化。然而，在小鼠脑中，p38 MAPK信号通路是否参与α 7 nAChR介导的A β内化的调节以及它们在线粒体中的作用仍然知之甚少。因此，在这项研究中，我们发现，A β是由胆碱能和GABA能神经元内化。发现内化的A β沉积在溶酶体/内体和线粒体中。A β可与α 7 nAChR形成A β-α 7 nAChR复合物，激活p38丝裂原活化蛋白激酶（MAPK）。而α 7 nAChR的增加又反过来介导了A β在皮层和海马的内化。此外，α 7 nAChR激动剂PNU 282987可降低p38磷酸化水平，挽救与A β诱导的细胞凋亡密切相关的生化变化，如Bcl 2/Bax水平、细胞色素c（Cyt c）释放等。总的来说，p38 MAPK信号通路可以调节α 7 nAChR介导的A β内化。激活α 7 nAChR或抑制p38 MAPK信号通路可能是治疗AD的有效途径。
Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. Intracellular beta-amyloid protein (A beta) is an early event in AD. It induces the formation of amyloid plaques and neuron damage. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) has been suggested to play an important role in A beta caused cognition. It has high affinity with A beta and could mediate A beta internalization in vitro. However, whether in mouse brain the p38 MAPK signaling pathway is involved in the regulation of the alpha 7nAChR mediated A beta internalization and their role in mitochondria remains little known. Therefore, in this study, we revealed that A beta is internalized by cholinergic and GABAergic neurons. The internalized A beta were found deposits in lysosomes/endosomes and mitochondria. A beta could form A beta-alpha 7nAChR complex with alpha 7nAChR, activates the p38 mitogen activated protein kinase (MAPK). And the increasing of alpha 7nAChR could in return mediate A beta internalization in the cortex and hippocampus. In addition, by using the alpha 7nAChR agonist PNU282987, the p38 phosphorylation level decreases, rescues the biochemical changes which are tightly associated with A beta-induced apoptosis, such as Bcl2/Bax level, cytochrome c (Cyt c) release. Collectively, the p38 MAPK signaling pathway could regulate the alpha 7nAChR-mediated internalization of A beta. The activation of alpha 7nAChR or the inhibition of p38 MAPK signaling pathway may be a beneficial therapy to AD.