Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Drugs Aging. 2010 Mar 1;27(3):181-92. doi: 10.2165/11532140-000000000-00000.
The complexities that underlie the cognitive impairment and neurodegeneration characteristic of Alzheimer's disease (AD) have yet to be completely understood, although many factors in disease pathogenesis have been identified. Particularly important in disease development seem to be mitochondrial disturbances. As pivotal role players in cellular metabolism, mitochondria are pertinent to cell survival and thus any deviation from their operation is certainly fatal. In this review, we describe how the dynamic balance of mitochondrial fission and fusion in particular is a necessary aspect of cell proliferation and that, as the cell ages, such balance is inevitably compromised to yield a destructive environment in which the cell cannot exist. Evidence for such disturbance is abundant in AD. Specifically, the dynamic balance of fission and fusion in AD is greatly shifted toward fission, and, as a result, affected neurons contain abnormal mitochondria that are unable to meet the metabolic demands of the cell. Moreover, mitochondrial distribution in AD cells is perinuclear, with few metabolic organelles in the distal processes, where they are normally distributed in healthy cells and are needed for exocytosis, ion channel pumps, synaptic function and other activities. AD neurons are thus characterized by increases in reactive oxidative species and decreases in metabolic capability, and, notably, these changes are evident very early in AD progression. We therefore believe that oxidative stress and altered mitochondrial dynamics contribute to the precipitation of AD pathology and thus cognitive decline. These implications provide a window for therapeutic intervention (i.e. mitochondrial protection) that has the potential to significantly deter AD progression if adequately developed. Current treatment strategies under investigation are described in this review.
阿尔茨海默病（AD）的认知障碍和神经退行性变的根本复杂性尚未完全理解，尽管已经确定了许多发病机制中的因素。在疾病发展中特别重要的似乎是线粒体紊乱。作为细胞代谢的关键角色扮演者，线粒体与细胞存活有关，因此任何偏离其运作的情况肯定是致命的。在这篇综述中，我们描述了线粒体分裂和融合的动态平衡是细胞增殖的必要方面，并且随着细胞衰老，这种平衡不可避免地受到损害，产生了细胞无法生存的破坏性环境。AD 中有大量的证据证明了这种紊乱。具体来说，AD 中分裂和融合的动态平衡大大偏向于分裂，结果是受影响的神经元含有无法满足细胞代谢需求的异常线粒体。此外，AD 细胞中的线粒体分布在核周，在远端过程中很少有代谢细胞器，而在健康细胞中它们通常分布在那里，并且对于胞吐作用、离子通道泵、突触功能和其他活动是必需的。因此，AD 神经元的特点是活性氧物种增加和代谢能力下降，值得注意的是，这些变化在 AD 进展的早期就很明显。因此，我们认为氧化应激和线粒体动力学的改变导致了 AD 病理和认知能力下降的发生。这些影响为治疗干预（即线粒体保护）提供了一个窗口，如果得到充分发展，有可能显著阻止 AD 的进展。本综述描述了正在研究中的当前治疗策略。
