Mechanistic Basis of Phenothiazine-Driven Inhibition of Tau Aggregation
Mechanistic Basis of Phenothiazine-Driven Inhibition of Tau Aggregation
复制标题
DOI：
10.1002/anie.201208290
复制
发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Zweckstetter, Markus
中科院分区：
文献类型：
--
作者：
Akoury, Elias;Pickhardt, Marcus;Zweckstetter, Markus
阿尔茨海默病-S病(AD)是最普遍的痴呆综合征，表现为细胞外大量的老年性β-淀粉样多肽(A-β)斑块和细胞内由Tau蛋白组成的神经纤维缠结(NFT)的沉积。[1，2]Tau蛋白是一种内在的无序蛋白质，它丰富地存在于神经元轴突中，促进和稳定微管组装。[3]随着AD的进展，Tau聚集并积聚成NFT。[2]由于目前仍没有对AD和其他神经病的病因治疗或治愈，基于Tau的研究旨在揭示淀粉样蛋白形成的病理后果并实施新的治疗策略。在这项工作中，确定tau聚集的抑制剂作为潜在的疾病修饰药物并研究它们的作用模式起着重要的作用。[4]亚甲蓝(MB)，一种三环吩噻嗪，也称为甲硫氨酸盐酸盐，[5]有超过100年的不同医疗应用的历史，包括用于不同的细胞靶点。[6]MB已被证明在体外防止Tau聚集[6-8]，并在线虫的Tau病理模型中减少Tau聚集的数量。[9]这种治疗减轻了Tau诱导的被处理蠕虫的毒性。MB在人类AD患者中进行了第二阶段的临床试验，结果令人振奋[10]，最近宣布进入第三阶段临床
Alzheimer s disease (AD) is the most widespread dementia syndrome showing progressive presence of abundant deposits of extracellular senile β-amyloid polypeptide (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) consisting of Tau protein.[1, 2] Tau protein is an intrinsically disordered protein that is abundant in neuronal axons where it promotes and stabilizes microtubule assembly.[3] With progression of AD, Tau aggregates and accumulates into NFTs.[2] As there is still no causative treatment or cure for AD and other tauopathies, Tau-based research aims to reveal the pathological consequences of amyloid formation and to implement new therapeutic strategies. In this effort, identification of inhibitors of tau aggregation as potential disease-modifying drugs and investigation of their mode of action play an important role.[4]Methylene Blue (MB), a tricyclic phenothiazine also known as methylthionine hydrochloride,[5] has a history of diverse medical applications stretching back over 100 years, including use for distinctive cellular targets.[6] MB has been shown to prevent Tau aggregation in vitro [6–8] and to reduce the amount of Tau aggregates in a C. elegans model of Tau pathology.[9] This treatment has relieved Tau-induced toxicity of treated worms.[9] Moreover, MB progressed to phase 2 clinical trials in human AD patients with promising results [10] and was recently announced to enter a phase3 clinical