Salvadores Natalia, Sanhueza Mario, Manque Patricio, Court Felipe A
Center for Integrative Biology, Faculty of Sciences, Universidad MayorSantiago, Chile.
Fondap Geroscience Center for Brain Health and MetabolismSantiago, Chile.
Front Neurosci. 2017 Sep 4;11:451. doi: 10.3389/fnins.2017.00451. eCollection 2017.
Aging constitutes the main risk factor for the development of neurodegenerative diseases. This represents a major health issue worldwide that is only expected to escalate due to the ever-increasing life expectancy of the population. Interestingly, axonal degeneration, which occurs at early stages of neurodegenerative disorders (ND) such as Alzheimer's disease, Amyotrophic lateral sclerosis, and Parkinson's disease, also takes place as a consequence of normal aging. Moreover, the alteration of several cellular processes such as proteostasis, response to cellular stress and mitochondrial homeostasis, which have been described to occur in the aging brain, can also contribute to axonal pathology. Compelling evidence indicate that the degeneration of axons precedes clinical symptoms in NDs and occurs before cell body loss, constituting an early event in the pathological process and providing a potential therapeutic target to treat neurodegeneration before neuronal cell death. Although, normal aging and the development of neurodegeneration are two processes that are closely linked, the molecular basis of the switch that triggers the transition from healthy aging to neurodegeneration remains unrevealed. In this review we discuss the potential role of axonal degeneration in this transition and provide a detailed overview of the literature and current advances in the molecular understanding of the cellular changes that occur during aging that promote axonal degeneration and then discuss this in the context of ND.
衰老构成神经退行性疾病发生的主要风险因素。这是一个全球性的重大健康问题，由于人口预期寿命不断增加，预计只会加剧。有趣的是，轴突变性发生在神经退行性疾病（ND）的早期阶段，如阿尔茨海默病、肌萎缩侧索硬化症和帕金森病，正常衰老也会导致轴突变性。此外，衰老大脑中发生的一些细胞过程的改变，如蛋白质稳态、细胞应激反应和线粒体稳态，也可能导致轴突病变。有力的证据表明，轴突退变先于神经退行性疾病的临床症状出现，且发生在细胞体丢失之前，是病理过程中的早期事件，并为在神经元细胞死亡前治疗神经退行性变提供了潜在的治疗靶点。虽然正常衰老和神经退行性变的发展是两个密切相关的过程，但触发从健康衰老向神经退行性变转变的分子基础仍未揭示。在这篇综述中，我们讨论了轴突变性在这种转变中的潜在作用，并详细概述了促进轴突退变的衰老过程中发生的细胞变化的分子理解方面的文献和当前进展，然后在神经退行性疾病的背景下进行讨论。
