Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Royal Parade, Parkville 3010, Victoria, Australia.
J Clin Neurosci. 2010 Aug;17(8):1025-33. doi: 10.1016/j.jocn.2010.04.020. Epub 2010 May 26.
Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimer's disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine-threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.
神经原纤维缠结由异常过度磷酸化的 tau 蛋白组成，是阿尔茨海默病（AD）和相关 tau 病的标志。tau 过度磷酸化被认为会促进聚集，随后形成缠结。通过提高关键磷酸酶/的活性来增强 tau 的去磷酸化，从而减少 tau 的磷酸化，可能是 AD 的一种可行的临床策略。参与调节 tau 蛋白磷酸化的关键磷酸酶之一是丝氨酸-苏氨酸磷酸酶 PP2A。我们已经确定，亚硒酸钠可以作为 PP2A 的特异性激动剂，显著提高磷酸酶活性。亚硒酸钠急性处理神经母细胞瘤细胞或正常老年小鼠可迅速降低 tau 蛋白磷酸化。与对照组相比，亚硒酸钠处理的转 TAU441 小鼠在海马和杏仁核中的磷酸化和总 tau 水平明显降低，并且在 Morris 水迷宫任务中的空间学习和记忆能力显著提高。亚硒酸钠是一种具有良好口服生物利用度和良好中枢神经系统穿透特性的 PP2A 特异性激活剂。预计在不久的将来将在 AD 患者中进行临床研究。
