TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease
TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease
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7, 8-二羟基黄酮激活 TrkB 可增加突触 AMPA 亚基并改善阿尔茨海默病小鼠模型的空间记忆缺陷
DOI：
10.1111/jnc.13432
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发表时间：
2016-02-01
影响因子：
4.7
通讯作者：
Zeng, Yan
中科院分区：
文献类型：
--
作者：
Gao, Lei;Tian, Mi;Zeng, Yan
我们最近证实，选择性酪氨酸受体激酶B激动剂7，8-二羟基黄酮（7，8-DHF）激活酪氨酸受体激酶B（Trk B），可增加脆性X综合征突变小鼠突触表面α-氨基-3羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（AMPAR）AMPA受体亚单位GluR 1（GluA 1）亚单位的表达。本研究探讨了7，8-DHF对Tg 2576阿尔茨海默病（AD）小鼠模型记忆功能和突触结构的影响，并与突触中AMPAR蛋白水平的关系。该研究发现，长期口服7，8-DHF显著改善了Tg 2576小鼠的空间记忆，并使海马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GluA 1和GluA 2的表达增加。有趣的是，7，8-DHF对Tg 2576 AD脑中呈现的淀粉样前体蛋白或A β的衰减没有影响，但它激活TrkB受体及其下游信号包括CaMKII，Akt，Erk 1/2和cAMP反应元件结合蛋白的磷酸化。重要的是，cyclotraxin B（Trk B抑制剂）、U 0126（Ras-ERK通路抑制剂）、Wortmannin（Akt磷酸化抑制剂）和KN-93（CaMKII抑制剂）抵消了由7，8-DHF诱导的AMPAR亚基的增强的表达和磷酸化。总的来说，我们的结果表明，7，8-DHF作用于TrkB和解决学习和记忆障碍，在淀粉样蛋白前体蛋白转基因小鼠的淀粉样蛋白减少的情况下，部分通过改善突触结构和增强突触AMPAR。提示7，8-DHF的应用可能是改善AD患者认知功能的一种新途径。
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-3hydroxy- 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 A beta 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.