Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines
Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines
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DOI：
10.1073/pnas.93.20.11213
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发表时间：
1996-10-01
影响因子：
11.1
通讯作者：
Harrington, CR
中科院分区：
文献类型：
--
作者：
Wischik, CM;Edwards, PC;Harrington, CR
在阿尔茨海默病（AD）中，微管相关蛋白tau以指数方式重新分布成成对螺旋丝（PHF），形成神经元缠结，其与锥体细胞破坏和痴呆相关。AD中的无定形神经元沉积物和PHFs的特征在于通过重复结构域的聚集和内源性蛋白酶在Glu-391处的C-末端截短。我们表明，在tau蛋白通过重复结构域中的高亲和力结合位点的自聚集之后，可以在体外产生类似的蛋白水解稳定复合物。一旦开始，tau蛋白捕获可以通过在蛋白酶存在下接种截短的tau蛋白的进一步积累来传播。（亚甲蓝，MB），其通过阻断经由重复结构域的tau-tau结合相互作用来逆转蛋白酶抗性PHF的蛋白水解稳定性。尽管MB在比临床上可达到的浓度更高的浓度下具有抑制性，tau-tau结合测定用于鉴定Ki值在纳摩尔范围内的MB的去甲基衍生物，神经安定剂吩噻嗪是无活性的，Tau聚集抑制剂不影响tau-微管蛋白相互作用，其也通过重复结构域发生，我们的研究结果表明，可以开发生物选择性药剂以促进tau聚集体的蛋白水解降解并防止tau蛋白的降解。AD中tau捕获的进一步传播。
In Alzheimer disease (AD) the microtubule-associated protein tau is redistributed exponentially into paired helical filaments (PHFs) forming neurofibrillary tangles, which correlate with pyramidal cell destruction and dementia. Amorphous neuronal deposits and PHFs in AD are characterized by aggregation through the repeat domain and C-terminal truncation at Glu-391 by endogenous proteases, We show that a similar proteolytically stable complex can be generated in vitro following the self-aggregation of tau protein through a high-affinity binding site in the repeat domain. Once started, tau capture can be propagated by seeding the further accumulation of truncated tau in the presence of proteases, We have identified a nonneuroleptic phenothiazine previously used in man (methylene blue, MB), which reverses the proteolytic stability of protease-resistant PHFs by blocking the tau-tau binding interaction through the repeat domain, Although MB is inhibitory at a higher concentration than may be achieved clinically, the tau-tau binding assay was used to identify desmethyl derivatives of MB that have K-i values in the nanomolar range, Neuroleptic phenothiazines are inactive, Tau aggregation inhibitors do not affect the tau-tubulin interaction, which also occurs through the repeat domain, Our findings demonstrate that biologically selective pharmaceutical agents could be developed to facilitate the proteolytic degradation of tau aggregates and prevent the further propagation of tau capture in AD.