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 ≈ 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.

Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington's Disease.

There is currently no disease-modifying treatment for Huntington's disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.

Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice.

Proteolytic cleavage of the amyloid precursor protein (APP) into the Aß peptide has been an extensively researched mechanism for Alzheimer's disease, but the normal function of the protein is less understood. APP functions to regulate neuronal iron content by stabilizing the surface presentation of ferroportin-the only iron exporter channel of cells. The present study aims to quantify the contribution of APP to brain and peripheral iron by examining the lifetime impact on brain and liver iron levels in APP knockout mice. Consistent with previous reports, we found that wild-type mice exhibited an age-dependent increase in iron and ferritin in the brain, while no age-dependent changes were observed in the liver. APP ablation resulted in an exaggeration of age-dependent iron accumulation in the brain and liver in mice that was assessed at 8, 12, 18, and 22 months of age. Brain ferroportin levels were decreased in APP knockout mice, consistent with a mechanistic role for APP in stabilizing this iron export protein in the brain. Iron elevation in the brain and liver of APP knockout mice correlated with decreased transferrin receptor 1 and increased ferritin protein levels. However, no age-dependent increase in brain ferritin iron saturation was observed in APP-KO mice despite similar protein expression levels potentially explaining the vulnerability of APP-KO mice to parkinsonism and traumatic brain sequelae. Our results support a crucial role of APP in regulating brain and peripheral iron, and show that APP may act to oppose brain iron elevation during aging.