Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia.
J Alzheimers Dis. 2018;64(s1):S379-S395. doi: 10.3233/JAD-179944.
Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.
铁是生命中至关重要的过渡金属，也是大脑中含量最丰富的过渡金属。然而，铁作为一种有效的氧化还原循环金属的生物学用途也使它有潜力催化有害自由基的产生。这种“两面神”性质的铁要求对其代谢进行严格的细胞调节。这种调节在中枢神经系统中至关重要，铁在中枢神经系统过程中扮演着无数关键角色，包括线粒体能量转导、酶催化、线粒体功能、髓鞘形成、神经递质合成和分解代谢。大脑中铁平衡的失调会提高这种氧化还原活性金属的水平，导致金属的定位错误和对敏感细胞和亚细胞结构的灾难性氧化损伤。铁动态平衡失调与阿尔茨海默病（AD）以及其他主要神经退行性疾病的发病机制密切相关。尽管 AD 的社会负担不断增加，但仍没有有效的治疗方法，因此需要继续投资于药物开发和研究疾病发病机制的基础科学。针对大脑中的铁动态平衡失调是治疗潜在疾病的合理方法。本文我们提供了有关 AD 中涉及的已知和新兴铁相关机制的最新信息。我们总结了一些证据，表明除了细胞凋亡外，AD 中的神经元丢失还涉及“铁死亡”，这是一种新发现的铁依赖性和脂质过氧化依赖性形式的调控性坏死。铁死亡领域正在迅速发展，可能为 AD 具有潜在疾病修饰作用的未来药物开发提供关键见解。
