Shin Min-Kyoo, Kim Hong-Gi, Kim Kil-Lyong
Department of Biological Sciences, Sungkyunkwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon, Gyeonggi-Do 440-746, South Korea; Institute of Basic Science, Sungkyunkwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon, Gyeonggi-Do 440-746, South Korea.
Department of Biological Sciences, Sungkyunkwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon, Gyeonggi-Do 440-746, South Korea.
Neurosci Lett. 2015 May 19;595:63-8. doi: 10.1016/j.neulet.2015.03.070. Epub 2015 Apr 4.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which plays important roles in learning and memory formation and in protecting neurons from diverse neurotoxic insults, such as amyloid-beta (Aβ). Since BDNF expression is decreased in patients with Alzheimer's disease, various strategies have attempted to increase BDNF levels. In a previous study, we screened and identified a novel BDNF-modulating peptide (consisting of methionine-valine-glycine, named Neuropep-1) by a positional scanning-synthetic peptide combinatorial library (PS-SPCL). Neuropep-1 exhibited neuroprotective effects against in vitro and in vivo Alzheimer's disease models. Based on the previous PS-SPCL data, we modified the amino acid sequence of Neuropep-1 in this study to identify a more potent novel BDNF-modulating peptide. By replacing the valine in the second position with aspartic acid, the resulting Neuropep-4 was found to be highly effective in inducing BDNF expression even at concentrations of 1pM in the SH-SY5Y cell line and rat primary cortical neurons. In addition, among the tested peptides, Neuropep-4 provided neurons with the strongest protection against oligomeric and/or fibrillar Aβ1-42-induced cell death through BDNF upregulation. These results suggest the potential of Neuropep-4 as a therapeutic candidate for treating neurodegenerative diseases, such as AD.
脑源性神经营养因子（BDNF）是神经营养因子家族的一员，在学习和记忆形成以及保护神经元免受多种神经毒性损伤（如β-淀粉样蛋白（Aβ））方面发挥着重要作用。由于阿尔茨海默病患者的BDNF表达降低，人们尝试了各种策略来提高BDNF水平。在之前的一项研究中，我们通过位置扫描合成肽组合文库（PS-SPCL）筛选并鉴定了一种新型的BDNF调节肽（由蛋氨酸-缬氨酸-甘氨酸组成，命名为神经肽-1）。神经肽-1对体外和体内阿尔茨海默病模型均表现出神经保护作用。基于之前的PS-SPCL数据，我们在本研究中对神经肽-1的氨基酸序列进行了修饰，以鉴定一种更有效的新型BDNF调节肽。通过将第二个位置的缬氨酸替换为天冬氨酸，发现所得的神经肽-4即使在SH-SY5Y细胞系和大鼠原代皮质神经元中浓度为1pM时，也能高效诱导BDNF表达。此外，在测试的肽中，神经肽-4通过上调BDNF为神经元提供了最强的保护，使其免受寡聚和/或纤维状Aβ1-42诱导的细胞死亡。这些结果表明神经肽-4作为治疗神经退行性疾病（如AD）的候选药物具有潜力。
