Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.
Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.
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DOI：
10.1016/j.stemcr.2017.02.006
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发表时间：
2017-04-11
影响因子：
5.9
通讯作者：
Livesey FJ
中科院分区：
文献类型：
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作者：
Brownjohn PW;Smith J;Portelius E;Serneels L;Kvartsberg H;De Strooper B;Blennow K;Zetterberg H;Livesey FJ
人类干细胞模型有可能提供表型筛选的平台，以确定参与神经退行性疾病发病机制的候选治疗和细胞途径。淀粉样前体蛋白（APP）的加工和APP衍生的淀粉样β（Aβ）肽的积累是阿尔茨海默病（AD）的关键过程。我们设计了一个表型小分子筛选来鉴定21三体/唐氏综合征神经元（AD的一种复杂遗传模型）中APP加工的调节剂。我们确定了阿维菌素，通常用作驱虫剂，作为增加短Aβ肽相对产量的化合物，以牺牲更长、潜在毒性更大的肽为代价。进一步的研究表明，这种效应不是由于与负责Aβ产生的核心γ-分泌酶的相互作用。这项研究证明了在阿尔茨海默型痴呆的人类干细胞模型中进行表型药物筛选的可行性，并指出了间接调节APP加工的可能性，而不依赖于γ-分泌酶调节。阿尔茨海默病人类干细胞模型的表型药物筛选阿维菌素被鉴定为健康和疾病中APP加工的修饰剂阿维菌素以较长的毒性形式为代价增加短的Aβ肽效应与已知的阿维菌素靶点和核心γ-分泌酶复合物无关在这篇文章中，Livesey及其同事在阿尔茨海默病人类干细胞模型中进行了表型药物筛选。驱虫阿维菌素被鉴定为一个家族的化合物，其增加短Aβ肽的产生，而不是更长的毒性更大的Aβ形式。这种作用类似于现有的γ-分泌酶调节剂，但不依赖于核心γ-分泌酶复合物。
Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation. Phenotypic drug screening of a human stem cell model of Alzheimer's disease Avermectins identified as modifiers of APP processing in health and disease Avermectins increase short Aβ peptides at the expense of longer, toxic forms Effect is independent of known avermectin targets and the core γ-secretase complex In this article, Livesey and colleagues perform a phenotypic drug screen in a human stem cell model of Alzheimer's disease. The anthelminthic avermectins are identified as a family of compounds that increase the production of short Aβ peptides over longer more toxic Aβ forms. The effect is analogous to existing γ-secretase modulators, but is independent of the core γ-secretase complex.