Activation of β2-adrenergic receptor promotes dendrite ramification and spine generation in APP/PS1 mice
Activation of β2-adrenergic receptor promotes dendrite ramification and spine generation in APP/PS1 mice
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β(2)-肾上腺素能受体的激活促进 APP/PS1 小鼠树突分枝和脊柱生成
DOI：
10.1016/j.neulet.2016.11.022
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发表时间：
2017-01-01
影响因子：
2.5
通讯作者：
Zhao, Peng
中科院分区：
文献类型：
--
作者：
Chai, Gao-Shang;Wang, Yang-Yang;Zhao, Peng
阿尔茨海默氏病（AD）是最常见的神经退行性疾病，目前尚无有效治愈这种毁灭性疾病的方法。据报道，AD 大脑的几个区域中 β(2)-肾上腺素受体 (β(2)-AR) 和去甲肾上腺素水平下降。 β(2)AR的激活可以阻止β淀粉样蛋白(Aβ)介导的LTP（长时程增强）抑制，但其机制尚不完全清楚。在这里，我们使用 APP/PS1 小鼠来研究 β(2)AR 的激活是否可以重塑突触和/或树突可塑性。我们发现克仑特罗 (Glen) 激活 β(2)AR 可改善记忆缺陷，促进海马 CA1 神经元树突分枝和脊柱生成，同时上调突触后密度蛋白 95 (PSD95)、突触蛋白 1 和突触素。相反，通过 siRNA 抑制 β(2)AR 可以阻断 Clen 诱导的原代海马神经元树突分枝和树突棘的增加。此外，β(2)AR 的激活通过上调α-分泌酶活性和减少 APP Thr668 的磷酸化来减少脑淀粉样斑块。基于 β(2)AR 在树突分枝和脊柱生成、记忆缺陷和 AD 发病机制中的作用，设计用于激活 β(2)AR 的化合物可能有助于治疗 AD。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
Alzheimer's disease (AD) is the most common neurodegenerative disorder, and currently there is no effective cure for this devastating disease. Decreases in the levels of beta(2)-adrenoceptor (beta(2)-AR) and norepinephrine have been reported in several regions of AD brains. The activation of beta(2)AR can prevent the amyloid beta (A beta)-mediated inhibition of LTP (Long-term potentiation), but the mechanism is not fully understood. Here, we used APP/PS1 mice to study whether the activation of beta(2)AR could remodel synaptic and/or dendritic plasticity. We found that the activation of beta(2)AR by Clenbuterol (Glen) ameliorated memory deficits and promoted dendrite ramification and spine generation in hippocampal CA1 neurons, which was accompanied by the upregulation of postsynaptic density protein 95 (PSD95), synapsin 1 and synaptophysin. Conversely, the inhibition of beta(2)AR by a siRNA blocked the Clen-induced increase in dendrite ramification and dendritic spines in primary hippocampal neurons. Furthermore, the activation of beta(2)AR decreased cerebral amyloid plaques through the up-regulation of a-secretase activity and by decreasing the phosphorylation of APP at Thr668. Based on the roles of beta(2)AR in dendrite ramification and spine generation, memory deficits and AD pathogenesis, compounds designed to activate beta(2)AR might shed light on the cure of AD. (C) 2016 Elsevier Ireland Ltd. All rights reserved.