Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232-8725, United States.
Biochemistry. 2011 Nov 29;50(47):10328-42. doi: 10.1021/bi201371j. Epub 2011 Nov 2.
γ-Secretase modulators (GSMs) have received much attention as potential therapeutic agents for Alzheimer's disease (AD). GSMs increase the ratio between short and long forms of the amyloid-β (Aβ) polypeptides produced by γ-secretase and thereby decrease the amount of the toxic amyloid species. However, the mechanism of action of these agents is still poorly understood. One recent paper [Richter et al. (2010) Proc. Natl. Acad. Sci. U. S. A.107, 14597-14602] presented data that were interpreted to support direct binding of the GSM sulindac sulfide to Aβ(42), supporting the notion that GSM action is linked to direct binding of these compounds to the Aβ domain of its immediate precursor, the 99-residue C-terminal domain of the amyloid precursor protein (C99, also known as the β-CTF). Here, contrasting results are presented that indicate there is no interaction between monomeric sulindac sulfide and monomeric forms of Aβ42. Instead, it was observed that sulindac sulfide is itself prone to form aggregates that can bind nonspecifically to Aβ42 and trigger its aggregation. This observation, combined with data from previous work [Beel et al. (2009) Biochemistry48, 11837-11839], suggests both that the poor behavior of some NSAID-based GSMs in solution may obscure results of binding assays and that NSAID-based GSMs do not function by directly targeting C99. It was also observed that another GSM, flurbiprofen, fails to bind to monomeric Aβ42 or to C99 reconstituted into bilayered lipid vesicles. These results disfavor the hypothesis that these NSAID-based GSMs exert their modulatory effect by directly targeting a site located in the Aβ42 domain of free C99.
γ-分泌酶调节剂（GSMs）作为阿尔茨海默病（AD）的潜在治疗药物受到了广泛关注。GSMs 增加了 γ-分泌酶产生的短形式和长形式的淀粉样蛋白-β（Aβ）多肽的比例，从而减少了有毒淀粉样物质的量。然而，这些药物的作用机制仍不清楚。最近的一篇论文[Richter 等人（2010 年）Proc. Natl. Acad. Sci. U. S. A.107, 14597-14602]提出的数据被解释为支持 GSM 舒林酸硫醚与 Aβ（42）的直接结合，支持 GSM 作用与其直接结合的观点这些化合物与淀粉样前体蛋白（Aβ 的 immediate precursor，99 个残基的 C 端结构域）的 Aβ 结构域有关，C99 也称为β-CTF。在这里，提出了相反的结果，表明单体舒林酸硫醚与单体形式的 Aβ42 之间没有相互作用。相反，观察到舒林酸硫醚本身容易形成聚集体，可以非特异性地结合 Aβ42 并触发其聚集。这一观察结果，结合之前的工作数据[Beel 等人（2009 年）Biochemistry48, 11837-11839]，表明一些基于 NSAID 的 GSM 在溶液中的不良行为可能会掩盖结合测定的结果，并且基于 NSAID 的 GSM 并非通过直接靶向 C99 起作用。还观察到另一种 GSM，氟比洛芬，不能结合单体 Aβ42 或重组到双层脂质囊泡中的 C99。这些结果不支持这些基于 NSAID 的 GSM 通过直接靶向位于游离 C99 的 Aβ42 结构域中的一个位点发挥其调节作用的假设。
