Tohda Chihiro, Kogure Chisato, Nomoto Kaori, de Toledo Andreia, Yang Ximeng, Hirano Eiichi
Section of Neuromedical Science, Division of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
Research Institute Japan Bio Products Co., Ltd., Kurume, Japan.
Front Pharmacol. 2021 May 14;12:680652. doi: 10.3389/fphar.2021.680652. eCollection 2021.
We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer's disease models to evaluate its potency as a new anti-Alzheimer's disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aβ-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.
我们研究了七肽GPPGPAG对阿尔茨海默病模型中记忆改善和神经突再生的影响，以评估其作为一种新型抗阿尔茨海默病（AD）疗法的潜力。在Aβ处理的皮质神经元和AD小鼠模型5XFAD中评估了GPPGPAG的抗AD作用。将皮质神经元暴露于Aβ25 - 35三天会导致轴突和树突萎缩。用GPPGPAG处理可改善Aβ处理的皮质神经元的树突萎缩，但不能改善轴突萎缩。GPPGPAG处理后可增加Aβ1 - 42暴露下的突触后和突触前密度。对5XFAD小鼠口服GPPGPAG 15天可显著改善物体识别记忆和树突密度。将GPPGPAG直接注入5XFAD小鼠侧脑室28天可改善物体识别记忆。在小鼠口服GPPGPAG后，在血浆和大脑皮质中检测到未消化的七肽。通过DARTS方法分析神经元中GPPGPAG的靶蛋白，确定14 - 3 - 3ε为结合蛋白。敲低14 - 3 - 3ε可消除GPPGPAG对Aβ1 - 42诱导的树突萎缩的保护作用。综上所述，这些结果表明GPPGPAG口服有效，可进入大脑，并改善AD大脑中的记忆功能障碍，这可能是由14 - 3 - 3ε相关的树突恢复介导的。
