Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease.
Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease.
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DOI：
10.1186/1750-1326-7-57
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发表时间：
2012-11-21
影响因子：
15.1
通讯作者：
Cherny RA
中科院分区：
文献类型：
--
作者：
McColl G;Roberts BR;Pukala TL;Kenche VB;Roberts CM;Link CD;Ryan TM;Masters CL;Barnham KJ;Bush AI;Cherny RA
阿尔茨海默病(AD)病理的决定性指标是大脑中淀粉样蛋白的大量积累。各种体外和基于细胞的模型已被提出用于高通量药物筛选，以期在蛋白质错误折叠疾病中获得潜在的治疗益处。秀丽线虫提供了一个方便的体内系统来检测复杂的多细胞生物体中的A？蓄积和毒性。这种动物模型易于培养，生命周期短，非常适合快速筛选候选化合物。我们已经产生了一种新的转基因线虫株系，它表达全长Aü1-42。该菌株不同于现有的主要表达氨基截短的A？3-42的A？模型。Aü1-42在体壁肌肉细胞中表达，在那里它寡聚、聚集并导致严重的、完全穿透性的进行性瘫痪。Aç1-42在体内的积累也显示为淀粉样染料阳性，这与体内纤维的形成一致。使用正在研究的阿尔茨海默病治疗药物PBT2检验了该模型在识别潜在保护化合物方面的实用性，该药物在AD小鼠模型中被证明具有神经保护作用，并显著改善AD患者的认知。我们观察到，PBT2处理提供了快速和显著的保护作用，以对抗阿伯诱导的线虫毒性。该线虫模型全长表达Aü1-42，现在可用于筛选，以快速识别和辅助开发潜在的治疗方法，并研究Aü的潜在毒性机制(S)。
The definitive indicator of Alzheimer’s disease (AD) pathology is the profuse accumulation of amyloid-ß (Aß) within the brain. Various in vitro and cell-based models have been proposed for high throughput drug screening for potential therapeutic benefit in diseases of protein misfolding. Caenorhabditis elegans offers a convenient in vivo system for examination of Aß accumulation and toxicity in a complex multicellular organism. Ease of culturing and a short life cycle make this animal model well suited to rapid screening of candidate compounds. We have generated a new transgenic strain of C. elegans that expresses full length Aß1-42. This strain differs from existing Aß models that predominantly express amino-truncated Aß3-42. The Aß1-42 is expressed in body wall muscle cells, where it oligomerizes, aggregates and results in severe, and fully penetrant, age progressive-paralysis. The in vivo accumulation of Aß1-42 also stains positive for amyloid dyes, consistent with in vivo fibril formation. The utility of this model for identification of potential protective compounds was examined using the investigational Alzheimer’s therapeutic PBT2, shown to be neuroprotective in mouse models of AD and significantly improve cognition in AD patients. We observed that treatment with PBT2 provided rapid and significant protection against the Aß-induced toxicity in C. elegans. This C. elegans model of full length Aß1-42 expression can now be adopted for use in screens to rapidly identify and assist in development of potential therapeutics and to study underlying toxic mechanism(s) of Aß.
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影响因子：
4.2
作者：
Link, CD;Johnson, CJ;Klunk, WE
通讯作者：
Klunk, WE
影响因子：
2.9
作者：
Klafki, HW;Wiltfang, J;Staufenbiel, M
通讯作者：
Staufenbiel, M
DOI：
10.1073/pnas.82.12.4245
发表时间：
1985-01-01
影响因子：
11.1
作者：
MASTERS, CL;SIMMS, G;BEYREUTHER, K
通讯作者：
BEYREUTHER, K
影响因子：
64.8
作者：
Duff, K;Eckman, C;Younkin, S
通讯作者：
Younkin, S
影响因子：
64.8
作者：
Alavez, Silvestre;Vantipalli, Maithili C.;Zucker, David J. S.;Klang, Ida M.;Lithgow, Gordon J.
通讯作者：
Lithgow, Gordon J.