Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Longevity Life Science and Technology Institutes, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
Neurobiol Dis. 2011 Nov;44(2):223-30. doi: 10.1016/j.nbd.2011.07.005. Epub 2011 Jul 18.
Alzheimer's disease (AD) is the major form of age-related dementia and is characterized by progressive cognitive impairment, the accumulation of extracellular amyloid β-peptide (Aβ), and intracellular hyperphosphorylated tau aggregates in affected brain regions. Tau hyperphosphorylation and accumulation in neurofibrillary tangles is strongly correlated with cognitive deficits, and is apparently a critical event in the dementia process because mutations in tau can cause a tangle-only form of dementia called frontotemporal lobe dementia. Among kinases that phosphorylate tau, glycogen synthase kinase 3β (GSK3β) is strongly implicated in AD pathogenesis. In the present study, we established an ELISA to screen for agents that inhibit GSK3β activity and found that the flavonoid morin effectively inhibited GSK3β activity and blocked GSK3β-induced tau phosphorylation in vitro. In addition, morin attenuated Aβ-induced tau phosphorylation and protected human neuroblastoma cells against Aβ cytotoxicity. Furthermore, treatment of 3xTg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons. Morin is a novel inhibitor of GSK3β that can reduce tau pathology in vivo and may have potential as a therapeutic agent in tauopathies.
阿尔茨海默病（AD）是与年龄相关的痴呆症的主要形式，其特征是进行性认知障碍、细胞外淀粉样 β 肽（Aβ）的积累以及受影响大脑区域中的细胞内过度磷酸化的 tau 聚集物。tau 在神经原纤维缠结中的过度磷酸化和积累与认知缺陷密切相关，显然是痴呆过程中的一个关键事件，因为 tau 的突变可导致仅出现缠结的痴呆形式，称为额颞叶痴呆。在磷酸化 tau 的激酶中，糖原合酶激酶 3β（GSK3β）强烈参与 AD 的发病机制。在本研究中，我们建立了一种 ELISA 来筛选抑制 GSK3β 活性的药物，发现黄酮醇桑色素可有效抑制 GSK3β 活性并阻止 GSK3β 诱导的 tau 磷酸化。此外，桑色素可减轻 Aβ 诱导的 tau 磷酸化并保护人神经母细胞瘤细胞免受 Aβ 的细胞毒性。此外，用桑色素治疗 3xTg-AD 小鼠可减少海马神经元中 tau 的过度磷酸化和双螺旋丝样免疫反应性。桑色素是 GSK3β 的一种新型抑制剂，可减少体内 tau 病理学，可能有作为 tau 病的治疗剂的潜力。
