Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
J Alzheimers Dis. 2011;26(3):565-81. doi: 10.3233/JAD-2011-110423.
Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-β (Aβ) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aβ-mediated neuronal toxicity. The observations that Aβ progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aβ in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Aβ-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aβ peptides induced an increase in NAD+levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aβ peptides. Our data shows for the first time that mitochondrial and cytosolic Aβ oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy.
线粒体功能障碍在阿尔茨海默病（AD）大脑和外周组织中都有观察到。已知淀粉样β（Aβ）肽与线粒体内部的几种蛋白质相互作用，导致线粒体功能障碍。最近的研究提供了大量证据表明，线粒体是 Aβ 介导的神经元毒性的直接靶标。观察到 Aβ 从 AD 患者和转基因 AD 型小鼠模型的皮质线粒体中逐渐积累，提示线粒体 Aβ 在 AD 的发病机制或发展中起作用。在此，我们研究了 Aβ 介导的线粒体代谢改变诱导的下游信号通路及其对细胞命运的影响。我们发现 Aβ 肽诱导 NAD+水平升高和 ATP 水平降低，这与乙酰化微管蛋白水平降低和 tau 过度磷酸化有关。由于微管的破坏，发现巨自噬发生改变，例如自噬体降解减少和 LC3B 的细胞分布改变。微管稳定剂紫杉醇能够恢复微管网络，并预防 Aβ 肽诱导的细胞死亡。我们的数据首次表明，微管动力学重建后，线粒体和细胞质 Aβ 低聚物显著减少。这些观察结果表明，在微管水平上进行干预可能是一种有效的疾病修饰治疗方法。
