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Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of A{beta}1-42 Mice via {alpha}7nAChR-Dependent BDNF Upregulation
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2022-08-03 , DOI: 10.1523/jneurosci.1989-21.2022
Chengyun Cai 1 , Lifeng Wang 2, 3 , Shixin Li 2, 3 , Shengchun Lou 2, 3 , Jia-Lie Luo 2, 3 , Ding-Yi Fu 2, 3 , Tingting Chen 3, 4
Affiliation  

Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ1-42 mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ1-42 mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ1-42 mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Aβ1-42 mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of α7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Aβ1-42 mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Aβ1-42 mice, which may be related to the improvement of BDNF content through the H-Ras-α7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition.

SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. However, no effective drugs have not been developed for the treatment of AD synaptic. This study for the first time reported the beneficial effects of Ras inhibitor lonafarnib on the synaptic structure and function in AD mice, providing an alternative way for the treatment of "synaptic disease" in AD patients.



中文翻译:


Ras 抑制剂 Lonafarnib 通过 {alpha}7nAChR 依赖性 BDNF 上调来拯救 A{beta}1-42 小鼠突触的结构和功能损伤



阿尔茨海默病(AD)的病理特征是海马突触的结构和功能损伤,导致学习和记忆缺陷。 Ras GTPase与突触功能和记忆密切相关。本研究旨在探讨法尼基转移酶抑制剂lonafarnib对AD雄性小鼠突触结构和功能的影响并探讨其潜在机制。我们的结果显示,50 mg/kg lonafarnib(腹膜内注射)可以挽救 Aβ 1-42小鼠受损的空间记忆并改善受损的突触传递和可塑性。此外,lonafarnib 还改善了 Aβ 1-42小鼠突触树突和棘的形态。此外,lonafarnib 增强 Aβ 1-42小鼠中的 α7nAChR 细胞表面表达以及下游 Akt 和 CaMKII 的磷酸化,这些表达可被 α7nAChR 拮抗剂甲基 lycaconitine (MLA) 抑制,并以 CaMKII 而非 ERK 依赖性方式增加 CREB ​​的磷酸化。 Lonafarnib 增强 Aβ 1-42小鼠海马脑源性神经营养因子 (BDNF) 浓度,该小鼠对 MLA 和 KN93(CaMKII 抑制剂)敏感,但与 ERK 和 Akt 通路无关。 H-Ras(而非 Rhes)与洛那法尼诱导的 α7nAChR 细胞表面表达和 BDNF 含量的改善有关。有趣的是,lonafarnib 在 Aβ 1-42小鼠中诱导的突触传递、可塑性和空间认知的改善被 TrkB/Fc 嵌合蛋白剥夺 BDNF 所消除。 我们的结果表明,lonafarnib可以挽救Aβ1-42小鼠突触的结构和功能损伤,这可能与通过H-Ras-α7nAChR依赖的CaMKII-CREB途径改善BDNF含量有关,从而导致神经元的改善的空间认知。


意义陈述阿尔茨海默病(AD)的病理特征是海马突触的结构和功能损伤,导致学习和记忆缺陷。然而,目前尚未开发出治疗AD突触的有效药物。该研究首次报道了Ras抑制剂lonafarnib对AD小鼠突触结构和功能的有益影响,为AD患者“突触疾病”的治疗提供了另一种途径。

更新日期:2022-08-04
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