Departamento de Farmacologia, Centro de ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Programa de Pós-Graduação em Neurociências, Centro de ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
J Alzheimers Dis. 2011;24(1):61-75. doi: 10.3233/JAD-2010-101320.
Early symptoms of Alzheimer's disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ₁₋₄₀-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aβ peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aβ₁₋₄₀ injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ₁₋₄₀. Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aβ₁₋₄₀ peptide.
阿尔茨海默病（AD）的早期症状归因于淀粉样蛋白-β（Aβ）毒性。AD 的病理生理学非常复杂，涉及几个不同的生化途径，包括缺陷的 Aβ 蛋白代谢、神经炎症、氧化过程和线粒体功能障碍。在本研究中，我们评估了分子机制，主要是线粒体复合物活性的改变，即叶酸和α-生育酚的联合保护作用可使小鼠免受 Aβ 诱导的神经毒性。连续 14 天每天口服叶酸（50mg/kg）加α-生育酚（500mg/kg）可防止 Aβ₁₋₄₀引起的认知衰退、突触丢失和神经元死亡。然而，叶酸加α-生育酚的慢性治疗对 Aβ 诱导的神经胶质细胞激活无效，表明这种治疗的效果与抗炎作用无关。有趣的是，我们研究的结果表明，Aβ 肽会损害线粒体能量代谢，上调线粒体基因可能是一种代偿反应，因为 Aβ₁₋₄₀ 注射后，小鼠海马中的线粒体复合物 I、II 和 IV 活性增加。值得注意的是，叶酸加α-生育酚的慢性治疗可防止 Aβ₁₋₄₀ 引起的线粒体复合物 I 和 IV 活性增加。总之，这些结果表明叶酸和α-生育酚的组合具有抗氧化作用，可观察到 iNOS 和 nNOS 生成的 NO 减少，防止线粒体复合物（主要是 I 和 IV）活性增加和 Aβ₁₋₄₀ 肽诱导的神经元死亡。
