Iron‐associated lipid peroxidation in Alzheimer's disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice

INTRODUCTION: Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimer's disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death. METHODS: To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed post mortem human brain and ApoEFAD mice. RESULTS: AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. Apolipoprotein E ε4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron in AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants. DISCUSSION: These novel molecular pathways highlight iron-mediated damage to lipid rafts during AD. HIGHLGHTS: Alzheimer's disease (AD) brains have numerous markers for ferroptosis, including increased lipid peroxidation, reduced antioxidant levels, and increased iron storage. Lipid rafts in AD cases have increased oxidative damage and reduced antioxidant enzyme levels and activity which are most severe in apolipoprotein E ε4 carriers. Neuronal markers are correlated with lipid peroxidation, antioxidant defense, and iron signaling proteins suggesting that neuronal loss is linked to these events. Chelation of iron in the early-onset familial AD model reduces iron-mediated lipid peroxidation and fibrillar amyloid.