Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy

• Published in: Molecular psychiatry Vol. 29; no. 2; pp. 211 - 220
• Main Authors: Belaidi, Abdel Ali, Masaldan, Shashank, Southon, Adam, Kalinowski, Pawel, Acevedo, Karla, Appukuttan, Ambili T., Portbury, Stuart, Lei, Peng, Agarwal, Puja, Leurgans, Sue E., Schneider, Julie, Conrad, Marcus, Bush, Ashley I., Ayton, Scott
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2024; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/51; 14/63; 631/378; 692/699; 82/80; 82/83; 96/31; Aged; Aged, 80 and over; AKT protein; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Autophagy; Autopsy; Behavioral Sciences; Biological Psychology; Brain - metabolism; Cell death; Cerebrospinal fluid; Cognitive ability; Female; Ferritin; Ferritins - metabolism; Ferroptosis; Ferroptosis - drug effects; Ferroptosis - physiology; Genotype; Genotypes; Health risk assessment; Humans; Iron; Iron - metabolism; Isoforms; Lipid peroxidation; Lipid Peroxidation - drug effects; Male; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neuroimaging; Neurons - metabolism; Neurosciences; Pharmacotherapy; Polyunsaturated fatty acids; Psychiatry; Temporal lobe
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-022-01568-w

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 (EC 50  ≈ 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 -ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 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.