Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid β Peptide
Non-chaperone Proteins Can Inhibit Aggregation and Cytotoxicity of Alzheimer Amyloid β Peptide
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DOI：
10.1074/jbc.m114.574947
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发表时间：
2014-10-03
影响因子：
4.8
通讯作者：
Abrahams, Jan Pieter
中科院分区：
文献类型：
--
作者：
Luo, Jinghui;Warmlander, Sebastian K. T. S.;Abrahams, Jan Pieter
背景：淀粉样蛋白的形成与阿尔茨海默病有关。结果：非伴侣蛋白阻止淀粉样蛋白的形成，降低A肽的细胞毒性。结论：非伴侣蛋白可能通过干扰A肽聚集影响阿尔茨海默病的发生和发展。意义：非伴侣蛋白可作为伴侣蛋白调控蛋白稳态中a纤颤的通路，为阿尔茨海默病的治疗提供新的策略。已知许多因素影响与阿尔茨海默病相关的A肽的寡聚化、纤颤和淀粉样蛋白形成。当A肽沉积在体内时存在的其他蛋白质可能对这些聚集过程有影响。为了区分蛋白质对A聚集的特异性和广谱效应，我们测试了一系列未报道具有伴侣活性的蛋白质：过氧化氢酶、丙酮酸激酶、白蛋白、溶菌酶、乳清蛋白和乳球蛋白。所有测试的蛋白质都以亚化学计量比抑制阿尔茨海默病A（1-40）肽的纤颤，尽管有些比其他更有效。所有蛋白质非特异性结合A，稳定其随机线圈，并降低其细胞毒性。令人惊讶的是，丙酮酸激酶和过氧化氢酶在抑制A聚集方面至少与已知的伴侣蛋白一样有效。我们提出了蛋白质广谱抑制A纤颤的一般机制。我们讨论的机制对预后，甚至对阿尔茨海默病的预防和治疗都有重要意义。
Background: A amyloid formation is associated with Alzheimer disease. Results: Non-chaperone proteins prevent amyloid formation and reduce the cytotoxicity of the A peptide. Conclusion: Non-chaperone proteins may affect the onset and development of Alzheimer disease by interfering with A peptide aggregation. Significance: Non-chaperone proteins can function as a chaperone protein to regulate the pathway of the A fibrillation in proteostasis providing a new strategy in the treatment of Alzheimer disease.Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the A peptide that is associated with Alzheimer disease. Other proteins that are present when A peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on A aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, -lactalbumin, and -lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer A(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to A, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting A aggregation. We propose general mechanisms for the broad-spectrum inhibition A fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.