A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease
A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease
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DOI：
10.3389/fnmol.2019.00310
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发表时间：
2019-12-12
影响因子：
4.8
通讯作者：
Reis, Robert J. Shmookler
中科院分区：
文献类型：
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作者：
Kakraba, Samuel;Ayyadevara, Srinivas;Reis, Robert J. Shmookler
年龄进行性神经退行性病变，包括阿尔茨海默病(AD)，通过细胞内或细胞外聚集的疾病特定成分来区分和诊断。越来越多的证据表明，神经炎症促进了蛋白质聚集，并参与了神经系统疾病的病因学。我们合成并测试了天然产生的微管蛋白结合化合物的类似物，comretasteatin A-4。其中一种类似物PNR502显著减少了BRI-A beta(1-42)AD小鼠模型中阿尔茨海默病相关淀粉样聚集体的数量，同时削弱了促炎细胞因子IL-1β在神经细胞培养模型中提高淀粉样斑块及其蛋白前体水平的能力。在肌肉或神经元表达人Aβ(1-42)的转基因秀丽线虫品系中，PNR502分别挽救了Aβ诱导的运动性(3.8倍，P<；0.0001)和趋化性(1.8倍，P<；0.05)中断。此外，在神经元表达Aβ(1-42)的线虫中，一天暴露于PNR502可逆转54%的趋化缺陷(P<；0.01)，实际上超过了长期暴露的保护。此外，连续使用PNR502可使线虫寿命延长23%(P
Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-A beta(1-42) mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1 beta to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human A beta(1-42) in muscle or neurons, PNR502 rescued A beta-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of A beta(1-42), a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P