Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Human Biology and Toxicology, Faculty of Medicine, University of Mons, Place du Parc 20, Mons, Belgium.
Redox Biol. 2020 May;32:101494. doi: 10.1016/j.redox.2020.101494. Epub 2020 Mar 5.
Iron dyshomeostasis is implicated in Alzheimer's disease (AD) alongside β-amyloid and tau pathologies. Despite the recent discovery of ferroptosis, an iron-dependent form cell death, hitherto, in vivo evidence of ferroptosis in AD is lacking. The present study uniquely adopts an integrated multi-disciplinary approach, combining protein (Western blot) and elemental analysis (total reflection X-ray fluorescence) with metabolomics (H nuclear magnetic resonance spectroscopy) to identify iron dyshomeostasis and ferroptosis, and possible novel interactions with metabolic dysfunction in age-matched male cognitively normal (CN) and AD post-mortem brain tissue (n = 7/group). Statistical analysis was used to compute differences between CN and AD, and to examine associations between proteins, elements and/or metabolites. Iron dyshomeostasis with elevated levels of ferritin, in the absence of increased elemental iron, was observed in AD. Moreover, AD was characterised by enhanced expression of the light-chain subunit of the cystine/glutamate transporter (xCT) and lipid peroxidation, reminiscent of ferroptosis, alongside an augmented excitatory glutamate to inhibitory GABA ratio. Protein, element and metabolite associations also greatly differed between CN and AD suggesting widespread metabolic dysregulation in AD. We demonstrate iron dyshomeostasis, upregulated xCT (impaired glutathione metabolism) and lipid peroxidation in AD, suggesting anti-ferroptotic therapies may be efficacious in AD.
铁代谢失衡与阿尔茨海默病（AD）中的β-淀粉样蛋白和 tau 病理学有关。尽管最近发现了铁依赖性细胞死亡形式——铁死亡，但迄今为止，AD 中存在铁死亡的体内证据仍然缺乏。本研究采用了独特的综合多学科方法，结合蛋白质（Western blot）和元素分析（全反射 X 射线荧光）与代谢组学（H 核磁共振波谱），以确定铁代谢失衡和铁死亡，以及与代谢功能障碍的可能新的相互作用在年龄匹配的男性认知正常（CN）和 AD 死后脑组织中（n = 7/组）。统计分析用于计算 CN 和 AD 之间的差异，并检查蛋白质、元素和/或代谢物之间的关联。AD 中存在铁代谢失衡，铁蛋白水平升高，而元素铁水平没有增加。此外，AD 的特征是半胱氨酸/谷氨酸转运体（xCT）的轻链亚基表达增强和脂质过氧化，类似于铁死亡，同时兴奋性谷氨酸与抑制性 GABA 的比值增加。蛋白质、元素和代谢物之间的关联在 CN 和 AD 之间也有很大差异，这表明 AD 中存在广泛的代谢失调。我们证明了 AD 中的铁代谢失衡、xCT 上调（谷胱甘肽代谢受损）和脂质过氧化，这表明抗铁死亡治疗可能对 AD 有效。
