Zhang Wei, Miao Jianting, Hao Jian, Li Zhen, Xu Jiang, Liu Rui, Cao Fale, Wang Ruirui, Chen Jun, Li Zhuyi
Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province, China.
Peptides. 2009 Jun;30(6):1197-202. doi: 10.1016/j.peptides.2009.02.017. Epub 2009 Mar 13.
Synaptic dysfunction induced by amyloid-beta protein (Abeta) has been shown to play a critical role in cognitive deficits of Alzheimer's disease (AD). Currently, however there is no clinical causative therapy for the disease. S14G-humanin (HNG) is best known for its strong neuroprotective ability against AD-related insults in vitro, and several in vivo studies have shown its effectiveness in ameliorating the cognitive impairment, but the precise mechanism of HNG on neuroprotection still remains to be elucidated. The present study examined the effects of HNG on Abeta-induced inhibition of hippocampal long-term potentiation (LTP) in mouse hippocampal slices. The results disclosed that soluble Abeta(25-35) significantly inhibited the induction of early-phase LTP (E-LTP) and late-phase LTP (L-LTP) in the hippocampal CA1 region without affecting the basal synaptic transmission, while HNG significantly ameliorated such inhibition of E-LTP and L-LTP in a dose-dependent manner. In addition, the reduction of phosphorylated CREB trigged by Abeta(25-35) was restored by HNG during L-LTP induction, possibly attributing to the improvement of the L-LTP inhibition. Collectively, our findings add to the evidence that soluble Abeta-induced LTP inhibition may represent an early pathological event of AD, and demonstrate for the first time that HNG may improve LTP inhibition by subneurotoxic concentration of soluble Abeta, suggesting that HNG may have therapeutic potential for Abeta-induced synaptic dysfunction closely associated with cognitive deficits in the early stage of AD.
β-淀粉样蛋白（Aβ）诱导的突触功能障碍已被证明在阿尔茨海默病（AD）的认知缺陷中起关键作用。然而，目前尚无针对该疾病的临床病因治疗方法。S14G-人胰岛素（HNG）以其在体外对AD相关损伤具有强大的神经保护能力而闻名，多项体内研究表明其在改善认知障碍方面有效，但HNG神经保护的确切机制仍有待阐明。本研究检测了HNG对Aβ诱导的小鼠海马切片海马长时程增强（LTP）抑制的影响。结果显示，可溶性Aβ（25-35）显著抑制海马CA1区早期LTP（E-LTP）和晚期LTP（L-LTP）的诱导，而不影响基础突触传递，而HNG以剂量依赖的方式显著改善了对E-LTP和L-LTP的这种抑制。此外，在L-LTP诱导过程中，HNG恢复了由Aβ（25-35）触发的磷酸化CREB的减少，这可能归因于L-LTP抑制的改善。总的来说，我们的研究结果进一步证明，可溶性Aβ诱导的LTP抑制可能代表AD的早期病理事件，并首次证明HNG可能改善亚神经毒性浓度的可溶性Aβ对LTP的抑制，表明HNG可能对与AD早期认知缺陷密切相关的Aβ诱导的突触功能障碍具有治疗潜力。
