H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment.
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.
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Fatima
F
Ali-Rahmani
Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Patricia S
PS
Grigson
Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Sang
S
Lee
Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Elizabeth
E
Neely
Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: jconnor@hmc.psu.edu.
James R
JR
Connor
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA. Electronic address: cxs8@psu.edu.
Cara-Lynne
CL
Schengrund
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000523:psychology; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008568:Memory; D008569:Memory Disorders / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology / Q000523:psychology; D021641:Recognition, Psychology; D012307:Risk Factors; D013250:Steroid Hydroxylases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D053327:Apolipoprotein E4; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D053148:Caspase 3
Alzheimer disease; Cholesterol; Hemochromatosis gene; Memory; Neurodegeneration