Chen Tsan-Ju, Wang Dean-Chuan, Chen Shun-Sheng
Department of Physiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Neurosci Res. 2009 Aug 1;87(10):2297-307. doi: 10.1002/jnr.22057.
The deposition of amyloid-beta (Abeta) contributes to the pathogenesis of Alzheimer's disease. Even at low levels, Abeta 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 Abeta 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 Abeta 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 Abeta. These results reveal that, in cultured rat cortical neurons, Abeta 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.
β-淀粉样蛋白（Aβ）的沉积促成了阿尔茨海默病的发病机制。即使在低水平时，Aβ也可能干扰对学习和记忆基础的突触可塑性至关重要的各种信号级联反应。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，Arc在调节突触可塑性中起重要作用。我们最近的研究表明，在非致死水平下用纤维状Aβ处理足以损害培养的大鼠皮质神经元中BDNF诱导的Arc表达。在本研究中，单独的BDNF处理诱导了磷脂酰肌醇3-激酶-蛋白激酶B-雷帕霉素哺乳动物靶标（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（eEF2）的去磷酸化以及Arc的表达。用抑制剂中断PI3K-Akt-mTOR信号通路可阻止BDNF的作用，表明该通路参与了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。大鼠皮质神经元中的双免疫荧光染色进一步证实，无论是否存在Aβ，BDNF处理后eEF2去磷酸化和Arc表达共存。这些结果表明，在培养的大鼠皮质神经元中，Aβ中断了可能参与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证据表明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。（c）2009威利-利斯公司。
