Matsuoka Yasuji, Jouroukhin Yan, Gray Audrey J, Ma Li, Hirata-Fukae Chiho, Li Hui-Fang, Feng Li, Lecanu Laurent, Walker Benjamin R, Planel Emmanuel, Arancio Ottavio, Gozes Illana, Aisen Paul S
Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057, USA.
J Pharmacol Exp Ther. 2008 Apr;325(1):146-53. doi: 10.1124/jpet.107.130526. Epub 2008 Jan 16.
Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.
由异常构象的聚集、过度磷酸化的tau蛋白组成的神经原纤维缠结是阿尔茨海默病（AD）和其他tau蛋白病的主要病理特征之一。然而，最近的数据表明，导致认知障碍的致病过程发生在经典缠结形成之前。在tau蛋白病的最早阶段，tau蛋白从微管上脱离并积聚在细胞体树突状区室的细胞质中。无论是作为原因还是结果，tau蛋白都会过度磷酸化并聚集成构成缠结的双螺旋丝。为了评估一种调节微管功能的药物是否能在具有AD相关tau蛋白病理的转基因小鼠模型中抑制致病过程并预防认知缺陷，我们给予了神经元微管优先药物NAPVSIPQ（NAP）。在tau蛋白病的早期到中期用NAP治疗三个月可降低过度磷酸化的可溶性和不溶性tau蛋白水平。六个月的疗程改善了认知功能。尽管常用于癌症治疗的非特异性微管相互作用药物因其抗有丝分裂活性而与不良反应相关，但在接触NAP六个月后未发现不良反应。我们的结果表明，像NAP这样的神经元微管相互作用药物可能是治疗或预防tau蛋白病的有用治疗药物。
