Luo Jinghui, Wärmländer Sebastian K T S, Gräslund Astrid, Abrahams Jan Pieter
From the Gorlaeus Laboratory, Leiden Institute of Chemistry, Leiden University, 2300RA Leiden, The Netherlands and.
Department of Biochemistry and Biophysics, Stockholm University SE-10691 Stockholm, Sweden.
J Biol Chem. 2014 Oct 3;289(40):27766-75. doi: 10.1074/jbc.M114.574947. Epub 2014 Aug 6.
Many factors are known to influence the oligomerization, fibrillation, and amyloid formation of the Aβ peptide that is associated with Alzheimer disease. Other proteins that are present when Aβ peptides deposit in vivo are likely to have an effect on these aggregation processes. To separate specific versus broad spectrum effects of proteins on Aβ aggregation, we tested a series of proteins not reported to have chaperone activity: catalase, pyruvate kinase, albumin, lysozyme, α-lactalbumin, and β-lactoglobulin. All tested proteins suppressed the fibrillation of Alzheimer Aβ(1-40) peptide at substoichiometric ratios, albeit some more effectively than others. All proteins bound non-specifically to Aβ, stabilized its random coils, and reduced its cytotoxicity. Surprisingly, pyruvate kinase and catalase were at least as effective as known chaperones in inhibiting Aβ aggregation. We propose general mechanisms for the broad-spectrum inhibition Aβ fibrillation by proteins. The mechanisms we discuss are significant for prognostics and perhaps even for prevention and treatment of Alzheimer disease.
已知许多因素会影响与阿尔茨海默病相关的Aβ肽的寡聚化、纤维化和淀粉样蛋白形成。当Aβ肽在体内沉积时存在的其他蛋白质可能会对这些聚集过程产生影响。为了区分蛋白质对Aβ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、α-乳白蛋白和β-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Aβ(1-40)肽的纤维化，尽管有些比其他的更有效。所有蛋白质都非特异性地与Aβ结合，稳定其无规卷曲，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Aβ聚集方面至少与已知的伴侣蛋白一样有效。我们提出了蛋白质对Aβ纤维化进行广谱抑制的一般机制。我们讨论的机制对阿尔茨海默病的预后甚至预防和治疗可能都具有重要意义。
