Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles E. Young Drive, Los Angeles, California 90095, USA.
Biochemistry. 2010 Feb 16;49(6):1259-67. doi: 10.1021/bi902075h.
A key event in Alzheimer's disease (AD) is age-dependent, brain accumulation of amyloid beta-protein (Abeta) leading to Abeta self-association into neurotoxic oligomers. Previously, we showed that Abeta oligomerization and neurotoxicity could be inhibited by C-terminal fragments (CTFs) of Abeta42. Because these CTFs are highly hydrophobic, we asked if they themselves aggregated and, if so, what parameters regulated their aggregation. To answer these questions, we investigated the dependence of CTF aqueous solubility, aggregation kinetics, and morphology on peptide length and sequence and the correlation between these characteristics and inhibition of Abeta42-induced toxicity. We found that CTFs up to 8 residues long were soluble at concentrations >100 microM and had a low propensity to aggregate. Longer CTFs were soluble at approximately 1-80 microM, and most, but not all, readily formed beta-sheet-rich fibrils. Comparison to Abeta40-derived CTFs showed that the C-terminal dipeptide I41-A42 strongly promoted aggregation. Aggregation propensity correlated with the previously reported tendency to form beta-hairpin conformation but not with inhibition of Abeta42-induced neurotoxicity. The data enhance our understanding of the physical characteristics that affect CTF activity and advance our ability to design, synthesize, and test future generations of inhibitors.
阿尔茨海默病（AD）的一个关键事件是年龄依赖性的，大脑中淀粉样β-蛋白（Abeta）的积累导致 Abeta 自组装成神经毒性寡聚物。以前，我们表明 Abeta 寡聚化和神经毒性可以被 Abeta42 的 C 端片段（CTFs）抑制。由于这些 CTFs 具有很强的疏水性，我们想知道它们本身是否会聚集，如果会，哪些参数会调节它们的聚集。为了回答这些问题，我们研究了 CTF 水溶解度、聚集动力学和形态对肽长度和序列的依赖性，以及这些特性与抑制 Abeta42 诱导的毒性之间的相关性。我们发现，长度达 8 个残基的 CTF 在浓度大于 100 μM 时是可溶的，并且聚集的倾向很低。较长的 CTF 在约 1-80 μM 时是可溶的，并且大多数（但不是全部）很容易形成富含β-折叠的纤维。与 Abeta40 衍生的 CTFs 比较表明，C 末端二肽 I41-A42 强烈促进聚集。聚集倾向与先前报道的形成β-发夹构象的趋势相关，但与抑制 Abeta42 诱导的神经毒性无关。这些数据增强了我们对影响 CTF 活性的物理特性的理解，并提高了我们设计、合成和测试新一代抑制剂的能力。
