Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Eur J Pharm Sci. 2017 Dec 15;110:101-108. doi: 10.1016/j.ejps.2017.03.037. Epub 2017 Mar 27.
Phosphorylated tau dissociates from microtubules and aggregates to form neurofibrillary tangles resulting in neuronal toxicity and cognitive deficits. Attenuating tau hyperphosphorylation is considered as an effective therapeutic approach for Alzheimer's disease (AD). From our previous study, SLM, a carbazole-based fluorophore prevents Aβ aggregation, reduced glycogen synthase kinase-3β (GSK-3β) activity and tau hyperphosphorylation in triple transgenic mouse model of AD. However, the mechanism by which SLM attenuates tau hyperphosphorylation warrants further investigation. In the current study, we intend to evaluate the effects of SLM against okadaic acid (OA)-induced tau hyperphosphorylation and microtubules instability in human neuroblastoma (SH-SY5Y) cells. The results showed that, SLM reduced the OA-induced cell neurotoxicity and tau hyperphosphorylation in SH-SY5Y cells. SLM treatment down-regulated GSK-3β activity. However, in the presence of GSK-3β inhibitor (SB216763, 10μM), SLM treatment could not reduce GSK-3β activity and tau hyperphosphorylation as compared with SB216763 treatment alone. Furthermore, SLM treatment also ameliorated OA-induced microtubules instability and cytoskeleton damage. Collectively, SLM attenuated OA-induced tau hyperphosphorylation via down-regulating GSK-3β activity in SH-SY5Y cells. Therefore, this study supports SLM as a potential compound for AD and other tau pathology-related neurodegenerative disorders.
磷酸化的 tau 从微管中分离出来并聚集形成神经原纤维缠结，导致神经元毒性和认知缺陷。减轻 tau 的过度磷酸化被认为是治疗阿尔茨海默病（AD）的有效方法。从我们之前的研究中可以看出，基于咔唑的荧光团 SLM 可防止 Aβ聚集，降低 AD 三转基因小鼠模型中的糖原合酶激酶-3β（GSK-3β）活性和 tau 的过度磷酸化。然而，SLM 减轻 tau 过度磷酸化的机制需要进一步研究。在目前的研究中，我们旨在评估 SLM 对冈田酸（OA）诱导的人神经母细胞瘤（SH-SY5Y）细胞 tau 过度磷酸化和微管不稳定的影响。结果表明，SLM 降低了 OA 诱导的 SH-SY5Y 细胞毒性和 tau 的过度磷酸化。SLM 处理下调了 GSK-3β 活性。然而，在存在 GSK-3β 抑制剂（SB216763，10μM）的情况下，与 SB216763 单独处理相比，SLM 处理不能降低 GSK-3β 活性和 tau 的过度磷酸化。此外，SLM 处理还改善了 OA 诱导的微管不稳定和细胞骨架损伤。总之，SLM 通过下调 SH-SY5Y 细胞中的 GSK-3β 活性来减轻 OA 诱导的 tau 过度磷酸化。因此，这项研究支持 SLM 作为一种潜在的化合物，用于治疗 AD 和其他与 tau 病理相关的神经退行性疾病。
