The Caenorhabditis elegans Aβ1-42 Model of Alzheimer Disease Predominantly Expresses Aβ3-42
The Caenorhabditis elegans Aβ1-42 Model of Alzheimer Disease Predominantly Expresses Aβ3-42
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DOI：
10.1074/jbc.c109.028514
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发表时间：
2009-08-21
影响因子：
4.8
通讯作者：
Bush, Ashley I.
中科院分区：
文献类型：
--
作者：
Mccoll, Gawain;Roberts, Blaine R.;Bush, Ashley I.
人类淀粉样蛋白β (A β)肽在秀丽隐杆线虫体壁肌细胞中的转基因表达已被用于更好地了解阿尔茨海默病（AD）的各个方面。在人类衰老和AD中，A β经历了翻译后的变化，包括共价修饰、截断和寡聚化。氨基截断的A β被越来越多地认为可能有助于AD的发病机制。在这里，我们描述了表面增强激光解吸电离飞行时间质谱法在已建立的转基因秀丽隐杆线虫系A β肽的质谱分析。令人惊讶的是，被表达的A β不是预期的全长1-42（氨基酸），而是3-42截断产物。体外分析表明，A β(3-42)与A β(1-42)一样具有自聚集性，但速度更快，并形成纤维状结构。同样，A β(3-42)也是A β(1-40)聚集的更有效的引发剂。通过A β(3-42)的种子聚集通过与过渡金属Cu（II）共孵育进一步增强。虽然出乎意料，但秀丽隐杆线虫的A β表达模型现在可以被用来研究A β的蛋白质毒性作用和加工（3-42）。
Transgenic expression of human amyloid beta (A beta) peptide in body wall muscle cells of Caenorhabditis elegans has been used to better understand aspects of Alzheimer disease (AD). In human aging and AD, A beta undergoes post-translational changes including covalent modifications, truncations, and oligomerization. Amino truncated A beta is increasingly recognized as potentially contributing to AD pathogenesis. Here we describe surface-enhanced laser desorption ionization-time of flight mass spectrometry mass spectrometry of A beta peptide in established transgenic C. elegans lines. Surprisingly, the A beta being expressed is not full-length 1-42 (amino acids) as expected but rather a 3-42 truncation product. In vitro analysis demonstrates that A beta(3-42) self-aggregates like A beta(1-42), but more rapidly, and forms fibrillar structures. Similarly, A beta(3-42) is also the more potent initiator of A beta(1-40) aggregation. Seeded aggregation via A beta(3-42) is further enhanced via co-incubation with the transition metal Cu(II). Although unexpected, the C. elegans model of A beta expression can now be co-opted to study the proteotoxic effects and processing of A beta(3-42).