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Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment
Experimental Neurology ( IF 5.3 ) Pub Date : 2021-07-16 , DOI: 10.1016/j.expneurol.2021.113812
Peiyun Yan 1 , Zhancheng Xue 2 , Dezhu Li 2 , Saiqi Ni 2 , Chuang Wang 3 , Xinchun Jin 4 , Dongsheng Zhou 5 , Xingxing Li 5 , Xin Zhao 3 , Xiaowei Chen 3 , Wei Cui 3 , Dingli Xu 1 , Wenhua Zhou 6 , Junfang Zhang 3
Affiliation  

Expression of CREB-regulated transcription coactivator 1 (CRTC1) in the hippocampus is impaired in Alzheimer's disease (AD). However, CRTC1 related mechanisms associated with long-term synaptic plasticity impairment and cognitive decline in the onset of AD are unknown. In this study, electrophysiological recordings indicated that lentivirus-mediated CRTC1 overexpression effectively ameliorates suppression of late-phase long-term potentiation (L-LTP) in rat hippocampal slices treated with oligomeric amyloid β(1–42) peptides (oAβ42) (200 nM). In addition, application of oAβ42 and genetic knockdown of CRTC1 by lentivirus-mediated CRTC1-shRNA inhibit L-LTP, whereas their combination does not further impair L-LTP. Brain-derived neurotrophic factor (BDNF), an important downstream protein confers protection of CRTC1 overexpression against oAβ42-induced L-LTP impairment as shown by administration of K252a (200 nM) and TrkB-FC (20 μg/ml). Furthermore, behavioral and western blotting analyses showed that CRTC1 overexpression reverses oAβ42-induced hippocampal-dependent cognitive deficits, downregulation of CRTC1 and BDNF expression. Notably, CRTC1-shRNA directly elicits cognitive deficits. In summary, these findings show that hippocampal CRTC1 signaling is affected by soluble oAβ, and CRTC1-BDNF pathway is involved in hippocampal L-LTP impairment and memory deficits induced by oAβ42.



中文翻译:

海马中 CRTC1-BDNF 信号通路失调导致 Aβ 寡聚体诱导的长期突触可塑性和记忆障碍

海马中 CREB ​​调节的转录辅激活因子 1 (CRTC1) 的表达在阿尔茨海默病 (AD) 中受损。然而,与 AD 发作时的长期突触可塑性障碍和认知能力下降相关的 CRTC1 相关机制尚不清楚。在这项研究中,电生理记录表明,慢病毒介导的 CRTC1 过表达有效地抑制了对用寡聚淀粉样蛋白 β(1-42) 肽 (oAβ42) (200 nM) 处理的大鼠海马切片中的晚期长时程增强 (L-LTP) 的抑制)。此外,oAβ42 的应用和慢病毒介导的 CRTC1-shRNA 对 CRTC1 的基因敲低抑制了 L-LTP,而它们的组合不会进一步损害 L-LTP。脑源性神经营养因子(BDNF),一种重要的下游蛋白赋予 CRTC1 过表达保护,防止 oAβ42 诱导的 L-LTP 损伤,如施用 K252a (200 nM) 和 TrkB-FC (20 μg/ml) 所示。此外,行为和蛋白质印迹分析表明,CRTC1 过表达逆转了 oAβ42 诱导的海马依赖性认知缺陷、CRTC1 和 BDNF 表达的下调。值得注意的是,CRTC1-shRNA 直接引起认知缺陷。总之,这些发现表明海马 CRTC1 信号受可溶性 oAβ 的影响,并且 CRTC1-BDNF 通路参与了由 oAβ42 诱导的海马 L-LTP 损伤和记忆缺陷。行为和蛋白质印迹分析显示 CRTC1 过表达逆转 oAβ42 诱导的海马依赖性认知缺陷、CRTC1 和 BDNF 表达的下调。值得注意的是,CRTC1-shRNA 直接引起认知缺陷。总之,这些发现表明海马 CRTC1 信号受可溶性 oAβ 的影响,并且 CRTC1-BDNF 通路参与了由 oAβ42 诱导的海马 L-LTP 损伤和记忆缺陷。行为和蛋白质印迹分析显示 CRTC1 过表达逆转 oAβ42 诱导的海马依赖性认知缺陷、CRTC1 和 BDNF 表达的下调。值得注意的是,CRTC1-shRNA 直接引起认知缺陷。总之,这些发现表明海马 CRTC1 信号受可溶性 oAβ 的影响,并且 CRTC1-BDNF 通路参与了由 oAβ42 诱导的海马 L-LTP 损伤和记忆缺陷。

更新日期:2021-07-26
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