The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.
The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice.
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DOI：
10.1186/s13195-020-00743-x
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发表时间：
2021-01-04
期刊：
影响因子：
--
通讯作者：
Bitan G
中科院分区：
文献类型：
--
作者：
Di J;Siddique I;Li Z;Malki G;Hornung S;Dutta S;Hurst I;Ishaaya E;Wang A;Tu S;Boghos A;Ericsson I;Klärner FG;Schrader T;Bitan G
分子钳(MTS)是蛋白质异常聚集的广谱抑制剂。一种名为CLR01的先导MT已被证明在体外和体内都能抑制多种淀粉样蛋白的聚集和毒性。此前，我们评估了CLR01在阿尔茨海默病3 × TG小鼠模型中的作用，该模型过度表达突变的人类早老素1、淀粉样蛋白前体和tau，发现皮下注射该化合物1个月可显著减少淀粉样斑块、神经原纤维缠结和小胶质细胞增生。CLR01在体外也被证明可以抑制tau的聚集和在细胞培养中接种tau，但由于在阿尔茨海默病(AD)和3 × TG模型中，tau的过度磷酸化和聚集被认为是Aβ损伤的下游，该模型的研究留下了一个悬而未决的问题，即CLR01是否直接或间接地影响体内的tau。为了确定CLR01是否可以在体内直接改善tau的病理，我们使用P301S-tau(线PS19)小鼠模型进行了类似的测试。小鼠每天给予0.3或1.0 mg/kg的CLR01，并测试肌肉力量和行为缺陷，包括焦虑和去抑制样行为。然后对他们的大脑进行免疫组织化学和生化分析，以确定tau的病理形式、神经退行性变和神经胶质病理。CLR01治疗改善了肌肉力量退化、焦虑和去抑制样行为。表型的改善与病理tau形式水平的降低有关，这表明CLR01在体内对tau有直接影响。这项研究的局限性包括，在小鼠尚未形成完整病理的年龄，其治疗期相对较短。此外，该模型的高度可变性降低了一些结果测量结果的统计意义。这些发现表明，CLR01是治疗AD的一个特别有吸引力的候选药物，因为它同时针对两种主要的致病蛋白，分别是淀粉样蛋白β蛋白(Aβ)和tau。此外，我们的研究表明，CLR01可用于治疗其他无淀粉样变性的肌萎缩侧索硬化症。网上版载有补充材料，可在10.1186/s13195-020-00743-x查阅。
Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly. To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology. CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures. The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology. The online version contains supplementary material available at 10.1186/s13195-020-00743-x.
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DOI：
10.1007/978-981-32-9358-8_30
发表时间：
2019-01-01
期刊：
TAU BIOLOGY
影响因子：
--
作者：
Buee, Luc
通讯作者：
Buee, Luc
影响因子：
4
作者：
Castillo-Carranza, Diana L.;Gerson, Julia E.;Kayed, Rakez
通讯作者：
Kayed, Rakez
影响因子：
2.5
作者：
GOEDERT, M;JAKES, R;VANMECHELEN, E
通讯作者：
VANMECHELEN, E
DOI：
10.1097/00005072-199906000-00011
发表时间：
1999-06-01
影响因子：
3.2
作者：
Bugiani, O;Murrell, JR;Ghetti, B
通讯作者：
Ghetti, B
影响因子：
4.2
作者：
Flood, Dorothy G.;Lin, Yin-Guo;Howland, David S.
通讯作者：
Howland, David S.