Laboratorio de Screening de Compuestos Neuroactivos, Universidad de Concepción, Concepción, Chile.
J Alzheimers Dis. 2012;31(4):879-89. doi: 10.3233/JAD-2012-120229.
Alzheimer's disease (AD) is characterized by the presence of different types of extracellular and neurotoxic aggregates of amyloid-β (Aβ). Recently, bioactive compounds extracted from natural sources showing neuroprotective properties have become of interest in brain neurodegeneration. We have purified, characterized, and evaluated the protective potential of one extract enriched in polyphenols obtained from Aristotelia chilensis (MQ), a Chilean berry fruit, in neuronal models of AD induced by soluble oligomers of Aβ1-40. For example, using primary hippocampal cultures from rats (E18), we observed neuroprotection when the neurons were co-incubated with Aβ (0.5 μM) plus MQ for 24 h (Aβ = 23 ± 2%; Aβ + MQ = 3 ± 1%; n = 3). In parallel, co-incubation of Aβ with MQ recovered the frequency of Ca2+ transient oscillations when compared to neurons treated with Aβ alone (Aβ = 72 ± 3%; Aβ + MQ = 86 ± 2%; n = 5), correlating with the changes observed in spontaneous synaptic activity. Additionally, MAP-2 immunostaining showed a preservation of the dendritic tree, suggesting that the toxic effect of Aβ is prevented in the presence of MQ. A new complex mechanism is proposed by which MQ induces neuroprotective effects including antioxidant properties, modulation of cell survival pathways, and/or direct interaction with the Aβ aggregates. Our results suggest that MQ induces changes in the aggregation kinetics of Aβ producing variations in the nucleation phase (Aβ: k1 = 2.7 ± 0.4 × 10-3 s-1 MQ: k1 = 8.3 ± 0.6 × 10-3 s-1) and altering Thioflavin T insertion in β-sheets. In conclusion, MQ induces a potent neuroprotection by direct interaction with the Aβ aggregates, generating far less toxic species and in this way protecting the neuronal network.
阿尔茨海默病(AD)的特征是存在不同类型的细胞外和神经毒性淀粉样β(Aβ)聚集物。最近,从天然来源提取的具有神经保护特性的生物活性化合物在大脑神经退行性变中引起了人们的兴趣。我们已经纯化、表征并评估了从智利莓(MQ)中提取的富含多酚的一种提取物的保护潜力,MQ 是智利的一种莓果,在由可溶性 Aβ1-40 寡聚物诱导的 AD 神经元模型中具有保护作用。例如,使用来自大鼠(E18)的原代海马培养物,当神经元与 Aβ(0.5 μM)和 MQ 共孵育 24 小时时,我们观察到神经保护作用(Aβ=23±2%;Aβ+MQ=3±1%;n=3)。同时,与单独用 Aβ处理的神经元相比,Aβ 与 MQ 共孵育恢复了 Ca2+瞬态振荡的频率(Aβ=72±3%;Aβ+MQ=86±2%;n=5),与观察到的自发突触活性变化相关。此外,MAP-2 免疫染色显示树突的保存,表明在 MQ 存在的情况下,Aβ 的毒性作用得到了预防。提出了一种新的复杂机制,通过该机制,MQ 诱导神经保护作用,包括抗氧化特性、调节细胞存活途径和/或与 Aβ 聚集物的直接相互作用。我们的结果表明,MQ 诱导 Aβ 聚集动力学的变化,导致成核阶段的变化(Aβ:k1=2.7±0.4×10-3s-1;MQ:k1=8.3±0.6×10-3s-1)并改变硫黄素 T 在β-折叠中的插入。总之,MQ 通过与 Aβ 聚集物的直接相互作用诱导强烈的神经保护作用,产生毒性小得多的物质,从而保护神经元网络。