Innovation Center for Neurological Disorders, Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.
Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.
J Alzheimers Dis. 2018;64(1):291-302. doi: 10.3233/JAD-180126.
Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.
越来越多的证据表明，线粒体功能障碍是阿尔茨海默病（AD）进展的一个突出早期事件。保护线粒体功能是否能降低 PS1V97L 转基因小鼠中淀粉样β寡聚物（AβO）诱导的神经毒性尚不清楚。在这项研究中，我们研究了霍诺醇（HKL）对神经元中 AβO 诱导的线粒体功能障碍以及 AD PS1V97L 转基因小鼠认知功能的可能保护作用。我们发现 HKL 增加了线粒体沉默调节蛋白 3（SIRT3）的表达水平和活性，从而显著提高了 ATP 的产生并减弱了线粒体活性氧的产生。我们证明，HKL 增强的能量代谢和减轻的氧化应激恢复了体外和体内 AβO 介导的线粒体功能障碍。因此，HKL 在早期挽救了 PS1V97L 转基因小鼠的记忆缺陷。这些结果表明，HKL 通过减轻线粒体损伤和增加 SIRT3 的过度激活，具有治疗 AD 症状发作的潜力，可用于治疗临床前 AD 的发病机制。
