Amyloid-β Interrupts the PI3K-Akt-mTOR Signaling Pathway That Could Be Involved in Brain-Derived Neurotrophic Factor-Induced Arc Expression in Rat Cortical Neurons
Amyloid-β Interrupts the PI3K-Akt-mTOR Signaling Pathway That Could Be Involved in Brain-Derived Neurotrophic Factor-Induced Arc Expression in Rat Cortical Neurons
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DOI：
10.1002/jnr.22057
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发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
Chen, Shun-Sheng
中科院分区：
文献类型：
--
作者：
Chen, Tsan-Ju;Wang, Dean-Chuan;Chen, Shun-Sheng
β 淀粉样蛋白 (Aβ) 的沉积有助于阿尔茨海默病的发病机制。即使水平较低，Aβ 也可能干扰对学习和记忆基础突触可塑性至关重要的各种信号级联。众所周知，脑源性神经营养因子（BDNF）能够诱导活性调节细胞骨架相关蛋白（Arc）的合成，该蛋白在调节突触可塑性方面发挥着重要作用。我们最近的研究表明，非致死水平的纤维 Aβ 治疗足以损害培养的大鼠皮层神经元中 BDNF 诱导的 Arc 表达。在本研究中，单独使用 BDNF 治疗可诱导磷脂酰肌醇 3-激酶-Akt-哺乳动物雷帕霉素靶标 (PI3K-Akt-mTOR) 信号通路的激活、真核起始因子 4E 结合蛋白 (4EBP1) 和 p70 核糖体 S6 激酶 (p70S6K) 的磷酸化、真核延伸因子 2 的去磷酸化(eEF2)，以及Arc的表达式。通过抑制剂中断 PI3K-Akt-mTOR 信号通路可阻止 BDNF 的作用，表明该通路参与 BDNF 诱导的 4EBP1 磷酸化、p70S6K 磷酸化、eEF2 去磷酸化和 Arc 表达。非致死性Aβ预处理部分阻断了BDNF的这些作用大鼠皮质神经元的双重免疫荧光染色进一步证实了BDNF治疗后eEF2去磷酸化和Arc表达的共存，无论Aβ是否存在。这些结果表明，在培养的大鼠皮质神经元中，Aβ 会中断可能参与 BDNF 诱导的 Arc 表达的 PI3K-Akt-mTOR 信号通路。此外，本研究还首次提供了BDNF诱导的eEF2去磷酸化与BDNF诱导的Arc表达之间存在密切相关性的证据。 (C) 2009 Wiley-Liss, Inc.
The deposition of amyloid-beta (A beta) contributes to the pathogenesis of Alzheimer's disease. Even at low levels, A beta may interfere with various signaling cascades critical for the synaptic plasticity that underlies learning and memory. Brain-derived neurotrophic factor (BDNF) is well known to be capable of inducing the synthesis of activity-regulated cytoskeleton-associated protein (Arc), which plays a fundamental role in modulating synaptic plasticity. Our recent study has demonstrated that treatment of fibrillar A beta at a nonlethal level was sufficient to impair BDNF-induced Arc expression in cultured rat cortical neurons. In this study, BDNF treatment alone induced the activation of the phosphatidylinositol 3-kinase-Akt-mammlian target of rapamycin (PI3K-Akt-mTOR) signaling pathway, the phosphorylation of eukaryotic initiation factor 4E binding protein (4EBP1) and p70 ribosomal S6 kinase (p70S6K), the dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the expression of Arc. Interrupting the PI3K-Akt-mTOR signaling pathway by inhibitors prevented the effects of BDNF, indicating the involvement of this pathway in BDNF-induced 4EBP1 phosphorylation, p70S6K phosphorylation, eEF2 dephosphorylation, and Arc expression. Nonlethal A beta pretreatment partially blocked these effects of BDNF Double-immunofluorescent staining in rat cortical neurons further confirmed the coexistence of eEF2 dephosphorylation and Arc expression following BDNF treatment regardless of the presence of A beta. These results reveal that, in cultured rat cortical neurons, A beta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in BDNF-induced Arc expression. Moreover, this study also provides the first evidence that there is a close correlation between BDNF-induced eEF2 dephosphorylation and BDNF-induced Arc expression. (C) 2009 Wiley-Liss, Inc.