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 (¹H 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.

铁失调与阿尔茨海默病 (AD) 以及 β-淀粉样蛋白和 tau 病理有关。尽管最近发现了铁死亡，但迄今为止，缺乏铁死亡在 AD中的体内证据，这是一种铁依赖性形式的细胞死亡。本研究独特地采用了综合的多学科方法，将蛋白质（蛋白质印迹）和元素分析（全反射 X 射线荧光）与代谢组学相结合（¹H 核磁共振波谱），以识别铁失衡和铁死亡，以及与年龄匹配的男性认知正常 (CN) 和 AD 死后脑组织 (n = 7/组) 中代谢功能障碍的可能新的相互作用。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。在没有增加元素铁的情况下，在 AD 中观察到铁蛋白水平升高的铁稳态失调。此外，AD 的特征是胱氨酸/谷氨酸转运蛋白 (xCT) 轻链亚基的表达增强和脂质过氧化，让人联想到铁死亡，同时兴奋性谷氨酸与抑制性 GABA 的比率增加。蛋白质，CN 和 AD 之间的元素和代谢物关联也有很大差异，表明 AD 中存在广泛的代谢失调。我们证明了 AD 中的铁稳态失调、xCT 上调（谷胱甘肽代谢受损）和脂质过氧化，表明抗铁死亡疗法可能对 AD 有效。