| First Author | Ali-Rahmani F | Year | 2014 |
| Journal | Neurobiol Aging | Volume | 35 |
| Issue | 6 | Pages | 1511.e1-12 |
| PubMed ID | 24439478 | Mgi Jnum | J:213886 |
| Mgi Id | MGI:5586782 | Doi | 10.1016/j.neurobiolaging.2013.12.014 |
| Citation | Ali-Rahmani F, et al. (2014) H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment. Neurobiol Aging 35(6):1511.e1-12 |
| abstractText | The H63D variant of the hemochromatosis (HFE) gene, when expressed in carriers of the apolipoprotein E4 allele, is implicated as a risk factor for earlier onset of Alzheimer's disease (AD). We tested the hypothesis that like expression of apolipoprotein E4, expression of H63D-HFE disrupts cholesterol metabolism contributing to an increase in neurodegeneration and memory deficits. Analysis of SH-SY5Y human neuroblastoma cells transfected to stably express either wild type- (WT) or H63D-HFE indicated about a 50% reduction in cholesterol content in cells expressing H63D-HFE. This was accompanied by a significant decrease in expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and a significant increase in expression of cholesterol 24-hydroxylase. Consistent with these studies, H67D-HFE (orthologous to human H63D-HFE) knock-in mice, showed a greater age dependent decline in brain cholesterol than WT-HFE animals and changes in expression of proteins regulating cholesterol metabolism. Brains of aged H67D-HFE mice also exhibited a significant decrease in expression of synapse proteins and a significant increase in caspase-3 expression relative to WT-HFE controls. H67D-HFE mice also had a greater reduction in brain volume and poorer recognition and spatial memory than WT-HFE mice, symptoms associated with AD. These results indicate that the alterations in cholesterol metabolism associated with expression of H63D-HFE may contribute to the development of AD. |
