Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3 beta Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson's Disease
Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3 beta Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson's Disease
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在 6-羟基多巴胺诱导的帕金森病模型中，人碱性成纤维细胞生长因子通过 PI3K/Akt-GSK3 beta 信号通路抑制 Tau 磷酸化
DOI：
10.1159/000445871
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发表时间：
2016
影响因子：
3
通讯作者：
Zhang Qi-hao
中科院分区：
文献类型：
--
作者：
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
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。由于这些疾病仍然没有治愈方法，因此确定新的治疗靶点和筛选潜在药物至关重要。tau在Ser 396处的磷酸化增加导致细胞内tau积累，其在帕金森病（PD）中形成神经元缠结。在这项研究中，bFGF的神经保护作用进行了观察，其调节磷酸化tau蛋白的机制进行了调查。MethodsbFGF负载的脂质体载体鼻内给药给大鼠。在6-羟基多巴胺（6-OHDA）诱导的PD模型中，在体内和体外评估bFGF的神经保护作用。结果脂质体可明显促进bFGF向纹状体和黑质的转运，增强bFGF对多巴胺能神经元的保护作用。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丢失，并增加了尼氏体的数量。结论脂质体可明显促进bFGF向脑内的转运，并通过抑制tau蛋白磷酸化增强bFGF的神经保护作用。bFGF通过PI 3 K/Akt信号通路促进GSK 3 β的磷酸化，从而下调tau蛋白的磷酸化。这些发现为碱性成纤维细胞生长因子作为帕金森病潜在治疗方法提供了新的视角。
BackgroundBasic 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 Ser 396 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.MethodsbFGF-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.ResultsOur 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.ConclusionLiposomes 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.