Alzheimer Disease Centre, Prague Psychiatric Centre, Ústavní 91, 181 03, Prague 8, Bohnice, Czech Republic.
Neurochem Res. 2012 Mar;37(3):604-13. doi: 10.1007/s11064-011-0650-8. Epub 2011 Nov 17.
Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric L-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural L-isoforms/synthetic D-isoforms on membranes are very similar, but synthetic reverse/random L: -isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated L-isoforms of amyloid β peptides 1-40/1-42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1-40 was evaluated by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid β; computational simulations were also performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with L-peptide 1-40 but not with the reverse L-peptide 40-1, (2) 24(R)hydroxycholesterol does not interact with L-peptide 1-40 or reverse 40-1, and (3) both enantiomers can probably interact with D-peptide 1-40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were found. Using this procedure, globular amyloid β could retain 24(S)hydroxycholesterol and thus contribute to its pathological accumulation in the brains of patients with Alzheimer disease.
β淀粉样肽似乎在生理过程中发挥作用；然而，它们也参与阿尔茨海默病的发病机制。在正常情况下，它们的作用可能是由低浓度的可溶性单体 L 异构体介导的，可能通过高度特异性的相互作用。相反，天然 L 异构体/合成 D 异构体聚集物对膜的毒性作用非常相似，但没有明显聚集特性的合成反向/随机 L：-异构体没有毒性。我们之前的工作报道了非聚集/聚集的淀粉样β肽 1-40/1-42 的 L 异构体与外消旋 24-羟胆固醇的相互作用。在这项研究中，通过基于海马胆固醇耗竭突触体中半胆碱-3 敏感高亲和力胆碱摄取系统对淀粉样β作用的易感性增加的体外试验，评估了天然 24(S)-羟基胆固醇（脑甾醇）或合成 24(R)-羟基胆固醇与可溶性片段 1-40 相互作用的立体特异性，还进行了计算模拟。我们的结果表明：(1)24(S)-羟基胆固醇与 L-肽 1-40 相互作用，但不与反向 L-肽 40-1 相互作用，(2)24(R)-羟基胆固醇不与 L-肽 1-40 或反向 40-1 相互作用，(3)两种对映体可能与 D-肽 1-40 相互作用。因此，24(S)-羟基胆固醇的结合不是完全立体特异性的，相互作用不能反映生理机制。计算模拟数据表明，淀粉样β分子的疏水区与 24(S)-羟基胆固醇的疏水区相互作用，但没有发现具有高稳定性的氢键。使用这种方法，球状淀粉样β可以保留 24(S)-羟基胆固醇，从而有助于其在阿尔茨海默病患者大脑中的病理性积累。
