Alzheimer’s disease ferroptotic associations with oxidative damage and neuronal loss

Abstract

ABSTRACTThe role of reactive iron in Alzheimer’s Disease (AD) remains unresolved. Little is known of how AD may alter iron transport, glutathione-mediated oxidative repair, and their associations with ApoE alleles. Postmortem brain intravascular blood was minimized by washing minced brain (n=24/group). HNE from iron-associated lipid peroxidation increased in AD prefrontal cortex by 50% for whole tissue and in subcellular lipid rafts, where Aβ-peptides are produced. HNE correlated with iron storage ferritin light chain (FTL; r=0.35); both were higher in ApoE4. Iron chelation by DFO in EFAD mice decreased HNE consistent with ferroptosis. Neuronal and synaptic loss in AD was inversely correlated to FTL (r=-0.55). AD decreased levels of ferroptosis suppressor protein 1, glutamate cysteine ligase modulator subunit (GCLM), and lipid raft glutathione peroxidase 4 (GPx4), mitigators of ferroptosis. These findings provide a mechanistic framework for iron-associated neurodegeneration during AD by impaired lipid peroxidation repair mechanisms involving glutathione.Graphical AbstractHypothesis: 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.