Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy

Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC50 approximate to 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-epsilon 4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of epsilon 4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the epsilon 4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.

Automated summary

Allelic variation to the APOE gene is the greatest genetic risk for sporadic Alzheimer's disease. Recent studies have found a link between APOE gene and brain iron, potentially through the ferroptosis pathway, to explain disease progression. Researchers discovered that apoE acts as a potent inhibitor of ferroptosis through activation of the PI3K/AKT pathway. Another study revealed that the APOE-epsilon 4 allele is more strongly associated with iron-related Alzheimer's disease, possibly due to lower levels of apoE protein and higher levels of polyunsaturated fatty acids.