Gao Lei, Tian Mi, Zhao Hong-Yun, Xu Qian-Qian, Huang Yu-Ming, Si Qun-Cao, Tian Qing, Wu Qing-Ming, Hu Xia-Min, Sun Li-Bo, McClintock Shawn M, Zeng Yan
Brain and Cognitive Dysfunction Research Center, School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
The Fifth Ward of Neurology Rehabilitation Center, Hangzhou Armed Police Hospital, Hangzhou, China.
J Neurochem. 2016 Feb;136(3):620-36. doi: 10.1111/jnc.13432. Epub 2015 Dec 29.
We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7, 8-DHF), the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8-DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease (AD) mouse model. The study found that chronic oral administration of 7, 8-DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect on the attenuation of amyloid precursor protein or Aβ exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras-ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a CaMKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8-DHF. Collectively, our results demonstrated that 7, 8-DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8-DHF may be a promising new approach to improve cognitive abilities in AD. We provided extensive data demonstrating that 7, 8-dihydroflavone, the TrkB agonist, improved Tg2576 mice spatial memory. This improvement is correlated with a reversion to normal values of GluA1 and GluA2 AMPA receptor subunits and dendritic spines in CA1. This work suggests that 7, 8-DHF is a suitable drug to potentiate in vivo Tropomyosin receptor kinase B (TrkB) signaling in the Alzheimer's disease mice model.
我们最近证明，选择性TrkB激动剂7,8 - 二羟基黄酮（7,8 - DHF）激活酪氨酸受体激酶B（TrkB），可增加脆性X综合征突变小鼠突触处的表面α-氨基-3 - 羟基-5 - 甲基-4 - 异恶唑丙酸（AMPA）受体（AMPARs）AMPAR亚基GluR1（GluA1）亚基的表达。本研究调查了7,8 - DHF对Tg2576阿尔茨海默病（AD）小鼠模型中记忆功能和突触结构的影响，以及与AMPARs突触蛋白水平的关系。研究发现，长期口服7,8 - DHF可显著改善Tg2576小鼠的空间记忆，并使海马体中的树突损失最小化。7,8 - DHF作用的一个关键特征是突触处GluA1和GluA2的表达增加。有趣的是，7,8 - DHF对Tg2576 AD大脑中淀粉样前体蛋白或Aβ的减少没有影响，但它激活了TrkB受体及其下游信号，包括CaMKII、Akt、Erk1/2和cAMP反应元件结合蛋白的磷酸化。重要的是，环孢菌素B（一种TrkB抑制剂）、U0126（一种Ras - ERK途径抑制剂）、渥曼青霉素（一种Akt磷酸化抑制剂）和KN - 93（一种CaMKII抑制剂）可抵消7,8 - DHF诱导的AMPAR亚基表达增强和磷酸化。总体而言，我们的结果表明，7,8 - DHF作用于TrkB，在淀粉样前体蛋白转基因小鼠中，在没有减少淀粉样蛋白的情况下，部分通过改善突触结构和增强突触AMPARs来解决学习和记忆障碍。这些发现表明，应用7,8 - DHF可能是改善AD认知能力的一种有前途的新方法。我们提供了大量数据证明，TrkB激动剂7,8 - 二氢黄酮改善了Tg2576小鼠的空间记忆。这种改善与CA1区GluA1和GluA2 AMPA受体亚基以及树突棘恢复到正常值相关。这项工作表明，7,8 - DHF是一种适合在阿尔茨海默病小鼠模型中增强体内原肌球蛋白受体激酶B（TrkB）信号传导的药物。
