Pitt Jason, Roth William, Lacor Pascale, Smith Amos B, Blankenship Matthew, Velasco Pauline, De Felice Fernanda, Breslin Paul, Klein William L
Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA.
Toxicol Appl Pharmacol. 2009 Oct 15;240(2):189-97. doi: 10.1016/j.taap.2009.07.018. Epub 2009 Jul 23.
It now appears likely that soluble oligomers of amyloid-beta1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Abeta oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Abeta species, when assayed with both sequence- and conformation-specific Abeta antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Abeta-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.
现在看来，β淀粉样蛋白1-42肽的可溶性寡聚体而非不溶性纤维，是阿尔茨海默病（AD）中的主要神经毒素。因此，能够改变这些寡聚体（称为ADDLs）组装状态的化合物可能具有AD治疗潜力。酚类化合物因其能够破坏β淀粉样蛋白寡聚化并降低致病性而备受关注。本研究聚焦于油橄榄苦素（OC），一种在特级初榨橄榄油中发现的天然酚类化合物。当用序列特异性和构象特异性β淀粉样蛋白抗体检测时，OC增加了可溶性β淀粉样蛋白物种的免疫反应性，表明寡聚体结构发生了变化。在OC存在下对寡聚体的分析显示分子量向上移动以及SDS稳定的ADDL亚物种呈阶梯状分布。与对照ADDLs相比，在OC存在下形成的寡聚体（β淀粉样蛋白-OC）在突触处显示出同等的共定位，但由于抗体识别增加而表现出更强的免疫荧光。突触处增强的信号并非由于突触结合增加，因为对荧光标记的ADDLs的直接检测显示在OC存在下ADDL信号总体减少。与突触结合减少相伴的是，通过drebrin丢失检测到的突触退化显著减少。此外，用OC处理改善了ADDLs的抗体清除。这些结果表明油橄榄苦素能够改变ADDLs的寡聚化状态，同时保护神经元免受ADDLs的突触病理效应影响，并表明OC作为AD治疗开发的先导化合物。
