Iron associated lipid peroxidation in Alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice
Iron associated lipid peroxidation in Alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice
ABSTRACT 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. To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed postmortem human brain and ApoEFAD mice. 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. ApoE4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron to 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. These novel molecular pathways in iron mediated damage during AD. Graphical Abstractbiorxiv;2023.03.28.534324v3/UFIG1F1ufig1Hypothesis: AD brain lipid peroxidation is driven by increased brain iron and decreased antioxidant defenses. Schema shows proteins that mediate iron metabolism in relation to lipid peroxidation (HNE) and antioxidant defenses in prefrontal cortex. AD-associated increase (red), decrease (blue), or no change (grey), relative to cognitively normal elderly controls. Aβ; amyloid beta, ALDH2; alcohol dehydrogenase, APP; amyloid precursor protein, DMT1; divalent metal transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1, which requires the quinol cycle to attenuate lipid peroxidation; FTH1, ferritin heavy chain; FTL; ferritin light chain; GCLC, glutathione cysteine ligase catalytic subunit; GCLM, glutathione cysteine ligase modulator; GPx4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; GSTA4, glutathione S-transferase A4; HMOX; heme oxygenase; IRP, iron regulatory protein; LAT1, large neutral amino acid transporter 1; LOOH, Lipid hydroperoxides; Nrf2, Nuclear factor erythroid 2-related factor 2; Prdx6, peroxiredoxin 6; TF, transferrin, TfR; Transferrin receptor; xCT, cysteine-glutamate antiporter.
Benayoun B¨|r¨|nice A.、Morgan Todd E.、Pike Christian J.、Higuchi-Sanabria Ryo、Forman Henry Jay、Thorwald Max A.、Head Elizabeth、O?ˉDay Peggy A.、Silva Justine、Garcia Gilberto、Mack Wendy J.、Godoy-Lugo Jose A.、Finch Caleb E.、Christensen Amy、Kim Minhoo
Leonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern California||School of Natural Sciences, University of California MercedLeonard Davis School of Gerontology, University of Southern CaliforniaDepartment of Pathology and Laboratory Medicine, University of CaliforniaLife and Environmental Sciences Department, University of CaliforniaDepartment of Pathology and Laboratory Medicine, University of CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaDepartment of Pediatrics, Keck School of Medicine of the University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern California||Dornsife College, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern CaliforniaLeonard Davis School of Gerontology, University of Southern California
基础医学神经病学、精神病学生物化学
GPx4GCLMFSP1HNEFerritinDeferoxamineEFADamyloid
Benayoun B¨|r¨|nice A.,Morgan Todd E.,Pike Christian J.,Higuchi-Sanabria Ryo,Forman Henry Jay,Thorwald Max A.,Head Elizabeth,O?ˉDay Peggy A.,Silva Justine,Garcia Gilberto,Mack Wendy J.,Godoy-Lugo Jose A.,Finch Caleb E.,Christensen Amy,Kim Minhoo.Iron associated lipid peroxidation in Alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2023.03.28.534324.点此复制
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