Yang Peng-Hui, Zhu Jian-Xiu, Huang Ya-Dong, Zhang Xian-Ying, Lei Peng, Bush Ashley I, Xiang Qi, Su Zhi-Jian, Zhang Qi-Hao
Institute of Biomedicine and National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.
Neurodegener Dis. 2016;16(5-6):357-69. doi: 10.1159/000445871. Epub 2016 May 27.
BACKGROUND: Basic fibroblast growth factor (bFGF) has been increasingly investigated due to its neuroprotection in neurodegenerative disorders. Because there are still no cures for any of these disorders, it is crucial to identify new therapeutic targets and screen potential drugs. The increased phosphorylation of tau at Ser396 leads to intracellular tau accumulation, which forms neurofibrillary tangles in Parkinson's disease (PD). In this study, neuroprotection by bFGF was observed, and the mechanisms related to its regulation of phosphorylated tau were investigated. METHODS: bFGF-loaded liposome carriers were intranasally administered to rats. The neuroprotective effects of bFGF were assessed in a PD model induced by 6-hydroxydopamine (6-OHDA) in vivo and in vitro. The phosphorylation of tau was measured, and the PI3K/Akt-GSK3β signaling pathway was investigated. RESULTS: Our study demonstrated that liposomes markedly assisted in the delivery of bFGF to the striatum and substantia nigra of rats and enhanced the neuroprotective effects of bFGF on dopaminergic neurons. bFGF treatment significantly ameliorated the behavioral deficits induced by 6-OHDA, rescued the loss of tyrosine hydroxylase-positive neurons and increased the number of Nissl bodies. bFGF reduced the phosphorylation of tau and GSK3β and increased the phosphorylation of PI3K/Akt. CONCLUSION: Liposomes markedly assisted in the delivery of bFGF to the brain and enhanced the neuroprotective effects of bFGF by inhibiting the phosphorylation of tau. bFGF down-regulated the phosphorylation of tau by increasing the phosphorylation of GSK3β via the PI3K/Akt signaling pathway. These findings provide a new vision of bFGF as a potential therapy for PD.
背景：碱性成纤维细胞生长因子（bFGF）因其在神经退行性疾病中的神经保护作用而受到越来越多的研究。由于这些疾病目前仍无法治愈，因此确定新的治疗靶点并筛选潜在药物至关重要。tau蛋白在Ser396位点的磷酸化增加会导致细胞内tau蛋白积累，进而在帕金森病（PD）中形成神经原纤维缠结。在本研究中，观察了bFGF的神经保护作用，并研究了其调节磷酸化tau蛋白的相关机制。 方法：将负载bFGF的脂质体载体经鼻给予大鼠。在体内和体外6-羟基多巴胺（6-OHDA）诱导的PD模型中评估bFGF的神经保护作用。检测tau蛋白的磷酸化情况，并研究PI3K/Akt-GSK3β信号通路。 结果：我们的研究表明，脂质体显著有助于bFGF向大鼠纹状体和黑质的递送，并增强了bFGF对多巴胺能神经元的神经保护作用。bFGF治疗显著改善了6-OHDA诱导的行为缺陷，挽救了酪氨酸羟化酶阳性神经元的损失，并增加了尼氏体的数量。bFGF降低了tau蛋白和GSK3β的磷酸化，并增加了PI3K/Akt的磷酸化。 结论：脂质体显著有助于bFGF向脑内递送，并通过抑制tau蛋白的磷酸化增强了bFGF的神经保护作用。bFGF通过PI3K/Akt信号通路增加GSK3β的磷酸化，从而下调tau蛋白的磷酸化。这些发现为bFGF作为PD的潜在治疗方法提供了新的视角。
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