Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions.
Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions.
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DOI：
10.1038/s41598-020-73680-2
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发表时间：
2020-10-06
影响因子：
4.6
通讯作者：
Kuo MH
中科院分区：
文献类型：
--
作者：
Liu M;Dexheimer T;Sui D;Hovde S;Deng X;Kwok R;Bochar DA;Kuo MH
神经退行性阿尔茨海默病（AD）影响全球3000多万人。迄今为止，还没有治疗或预防AD的方法。脑中过度磷酸化tau蛋白的聚集与AD和其他神经退行性tau蛋白病患者的认知下降相关。脑内注射从tau蛋白病脑中分离的tau聚集体在受体小鼠中引起类似的病理学，证明了异常磷酸化tau的致病作用。因此，控制过度磷酸化tau聚集的化合物可能是该疾病的调节剂。在这里，我们报告使用重组过度磷酸化tau蛋白（p-tau），以确定潜在的tau蛋白病的治疗和危险因素。过度磷酸化使tau易于聚集并损害细胞活力。利用p-tau的这两个特征，我们进行了1280个化合物库的筛选，并在p-tau聚集和细胞毒性测定中测试了一组选择性的处方药。发现R-（-）-阿扑吗啡和雷洛昔芬是保护p-tau处理的细胞的p-tau聚集抑制剂。相比之下，苯二氮卓类药物的一个子集明显通过增强p-tau聚集而加剧p-tau细胞毒性。R-（−）阿扑吗啡和雷洛昔芬已被证明可以改善动物或人类的认知能力，而苯二氮卓类药物则与痴呆症风险增加有关。我们的研究结果证明了使用基于过度磷酸化tau蛋白的检测方法进行AD药物发现和风险因素鉴定的可行性和潜力。
The neurodegenerative Alzheimer’s disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(−)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(−)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.
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DOI：
10.1074/jbc.m114.589309
发表时间：
2015-01-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
通讯作者：
Bose S
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1016/j.bbrc.2007.03.056
发表时间：
2007-06-22
影响因子：
3.1
作者：
Crowe, Alex;Ballatore, Carlo;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
DOI：
10.1016/s0140-6736(16)31275-2
发表时间：
2016-12-10
期刊：
Lancet (London, England)
影响因子：
--
作者：
Gauthier S;Feldman HH;Schneider LS;Wilcock GK;Frisoni GB;Hardlund JH;Moebius HJ;Bentham P;Kook KA;Wischik DJ;Schelter BO;Davis CS;Staff RT;Bracoud L;Shamsi K;Storey JM;Harrington CR;Wischik CM
通讯作者：
Wischik CM
DOI：
10.1136/bmj.g5205
发表时间：
2014-09-09
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Billioti de Gage S;Moride Y;Ducruet T;Kurth T;Verdoux H;Tournier M;Pariente A;Bégaud B
通讯作者：
Bégaud B