Alzheimer's Disease associations of ferritin and glutathione with oxidative damage and neuronal loss

The role of reactive iron in Alzheimer's Disease (AD) has major gaps. Little is known of AD changes in iron transport, glutathione-mediated oxidative repair, and associations with ApoE alleles. Intravascular blood was minimized by washing minced postmortem brains. HNE from iron-associated lipid peroxidation was increased in AD prefrontal cortex by 50% for whole tissue and subcellular lipid rafts, where Aβ-peptides are produced. Proteins mediating iron deposition and oxidative repair were extensively altered by AD. Protein oxidation was proportionate to the iron storage protein ferritin light chain (FTL); both higher in ApoE4. Loss of neurons and synapses in AD was proportionate to FTL. Iron transport was impaired with lower transferrin, transferrin receptor, and ferroportin. AD decreased Ferroptosis suppressor protein 1 and glutamate cysteine ligase modulator subunit (GCLM), which regulates glutathione synthesis. These findings provide a mechanistic framework for iron-associated neurodegeneration during AD through impairment of lipid peroxidation repair mechanisms involving glutathione. ### Competing Interest Statement The authors have declared no competing interest.