Intrinsic Determinants of Neurotoxic Aggregate Formation by the Amyloid β Peptide
Intrinsic Determinants of Neurotoxic Aggregate Formation by the Amyloid β Peptide
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DOI：
10.1016/j.bpj.2009.12.4320
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发表时间：
2010-04-21
影响因子：
3.4
通讯作者：
Luheshi, Leila M.
中科院分区：
文献类型：
--
作者：
Brorsson, Ann-Christin;Bolognesi, Benedetta;Luheshi, Leila M.
从纤维前低聚物到淀粉样原纤维，蛋白质聚集成不同结构的程度是许多与年龄相关的退行性疾病发病机制的关键。我们在这里描述了与阿尔茨海默病相关的β淀粉样蛋白肽（A β）的一项基于序列的决定因素的研究，该决定因素决定了纤维前聚集体和淀粉样原纤维形成之间的平衡。我们发现，通过引入单点突变，通常无害的A β(40)肽有可能通过增加其形成前纤维而不是纤维聚集体的相对倾向而转化为致病物种，相反，通过减少其形成前纤维而不是成熟纤维的相对倾向，可以消除高神经毒性的E22G A β(42)肽的致病性。这一观察结果可以通过以下证明来合理化：高聚集倾向序列的区域支配着总体聚集倾向，而具有低内在聚集倾向的区域对形成的原纤维和原纤维物种的平衡发挥着重要的控制作用，因此在决定a β肽的神经毒性方面发挥着重要作用。
The extent to which proteins aggregate into distinct structures ranging from prefibrillar oligomers to amyloid fibrils is key to the pathogenesis of many age-related degenerative diseases. We describe here for the Alzheimer's disease-related amyloid beta peptide (A beta) an investigation of the sequence-based determinants of the balance between the formation of prefibrillar aggregates and amyloid fibrils. We show that by introducing single-point mutations, it is possible to convert the normally harmless A beta(40) peptide into a pathogenic species by increasing its relative propensity to form prefibrillar but not fibrillar aggregates, and, conversely, to abolish the pathogenicity of the highly neurotoxic E22G A beta(42) peptide by reducing its relative propensity to form prefibrillar species rather than mature fibrillar ones. This observation can be rationalized by the demonstration that whereas regions of the sequence of high aggregation propensity dominate the overall tendency to aggregate, regions with low intrinsic aggregation propensities exert significant control over the balance of the prefibrillar and fibrillar species formed, and therefore play a major role in determining the neurotoxicity of the A beta peptide.