Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, Basel, Switzerland.
Antioxid Redox Signal. 2012 Jun 15;16(12):1456-66. doi: 10.1089/ars.2011.4400. Epub 2012 Jan 30.
Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-β [Aβ]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear.
A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD.
In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Aβ and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging, Aβ, and tau protein" triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease.
The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aβ and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.
阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，主要影响老年人。AD 的病理学特征是淀粉样斑块（淀粉样蛋白-β [Aβ]的聚集物）和神经原纤维缠结（tau 的聚集物），但导致这种功能障碍的机制仍部分不清楚。
越来越多的证据支持线粒体功能障碍作为一个突出的、早期的、与慢性氧化应激相关的事件，它导致突触异常，并最终导致 AD 中的选择性神经元变性。
在这篇综述中，我们一方面讨论了在大脑老化过程中观察到的线粒体下降是否是 AD 发病的决定因素，另一方面讨论了这种细胞器与 AD 发病过程中的 Aβ和 tau 之间的密切关系。此外，我们总结了衰老和阿尔茨海默病模型的证据，表明有害的“衰老、Aβ和 tau 蛋白”三重奏通过多种途径触发线粒体功能障碍，如氧化磷酸化（OXPHOS）受损、活性氧产生升高以及与线粒体蛋白相互作用，导致疾病的发展和进展。
衰老过程可能在多年内以更普遍的方式削弱线粒体 OXPHOS 系统，为 Aβ和 tau 的特异性和破坏性影响提供基础。通过稳定或恢复线粒体功能和能量稳态来保护细胞的线粒体水平的策略似乎具有挑战性，但在未来是一个非常有前景的方向。
