Spires-Jones Tara L, Friedman Taylor, Pitstick Rose, Polydoro Manuela, Roe Allyson, Carlson George A, Hyman Bradley T
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Neurosci Lett. 2014 Mar 6;562:63-8. doi: 10.1016/j.neulet.2014.01.013. Epub 2014 Jan 21.
Alzheimer's disease is characterized pathologically by aggregation of amyloid beta into senile plaques and aggregation of pathologically modified tau into neurofibrillary tangles. While changes in amyloid processing are strongly implicated in disease initiation, the recent failure of amyloid-based therapies has highlighted the importance of tau as a therapeutic target. "Tangle busting" compounds including methylene blue and analogous molecules are currently being evaluated as therapeutics in Alzheimer's disease. Previous studies indicated that methylene blue can reverse tau aggregation in vitro after 10 min, and subsequent studies suggested that high levels of drug reduce tau protein levels (assessed biochemically) in vivo. Here, we tested whether methylene blue could remove established neurofibrillary tangles in the rTg4510 model of tauopathy, which develops robust tangle pathology. We find that 6 weeks of methylene blue dosing in the water from 16 months to 17.5 months of age decreases soluble tau but does not remove sarkosyl insoluble tau, or histologically defined PHF1 or Gallyas positive tangle pathology. These data indicate that methylene blue treatment will likely not rapidly reverse existing tangle pathology.
阿尔茨海默病的病理特征是β-淀粉样蛋白聚集成老年斑，以及病理性修饰的tau蛋白聚集成神经原纤维缠结。虽然淀粉样蛋白加工过程的改变与疾病的起始密切相关，但最近基于淀粉样蛋白的治疗方法的失败凸显了tau作为治疗靶点的重要性。包括亚甲蓝和类似分子在内的“抗缠结”化合物目前正在作为阿尔茨海默病的治疗药物进行评估。先前的研究表明，亚甲蓝在体外10分钟后可逆转tau蛋白聚集，随后的研究表明，高剂量药物可在体内降低tau蛋白水平（通过生化方法评估）。在此，我们测试了亚甲蓝是否能清除tau蛋白病的rTg4510模型中已形成的神经原纤维缠结，该模型会出现严重的缠结病理。我们发现，在16个月至17.5个月龄时，在饮水中添加6周亚甲蓝可降低可溶性tau蛋白水平，但不能清除 Sarkosyl 不溶性tau蛋白，也不能清除组织学定义的PHF1或Gallyas阳性缠结病理。这些数据表明，亚甲蓝治疗可能无法迅速逆转现有的缠结病理。
