The H63D HFE gene variant promotes activation of the intrinsic apoptotic pathway via mitochondria dysfunction following β-amyloid peptide exposure.

Abstract

Numerous epidemiological studies suggest that the expression of the HFE allelic variant H63D may be a risk factor or genetic modifier for Alzheimer's disease (AD). The H63D variant alters cellular iron homeostasis and increases baseline oxidative stress. The elevated cellular stress milieu, we have proposed, may alter cellular responses to genetic and environmental determinants of AD. Accumulation of β-amyloid peptides (Aβ) is one of the most prominent pathogenic characteristics of AD. Several studies have demonstrated that Aβ can induce neuronal cell death through apoptosis. In this study, we provide evidence that an Aβ(25-35) fragment, which contains the cytotoxic sequence of the amyloid peptide, activates the intrinsic apoptotic pathway in SH-SY5Y human neuroblastoma cells expressing the HFE allelic variant H63D to a greater extent than in cells with wild-type (WT) HFE. Specifically, Aβ(25-35) peptide exposure significantly induced Bax translocation from the cytosol to the mitochondria in H63D-expressing cells compared with WT cells. This translocation was associated with increased cytochrome c release from mitochondria and an increase in active caspase-9 and caspase-3 activity in H63D cells. Consequently, there is increased apoptosis in cells expressing the H63D variant as opposed to cells expressing WT HFE. We also found increased amyloid precursor protein (APP) and Aβ(1-42) peptide in the mitochondrial compartment as well as increased mitochondrial stress in H63D-expressing cells compared with WT. These findings support our hypothesis that the presence of the HFE H63D allele enables factors that trigger neurodegenerative processes associated with AD and predisposes cells to cytotoxcity.

• Authors: Nootchanat Mairuae, Eric C Hall Ii, Poonlarp Cheepsunthorn, Sang Y Lee, James R Connor
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 88 Issue 14 Pg. 3079-89 (Nov 01 2010) ISSN: 1097-4547 [Electronic] United States
• PMID: 20734416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Wiley-Liss, Inc.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• HFE protein, human
• Hemochromatosis Protein
• Histocompatibility Antigens Class I
• Membrane Proteins
• Peptide Fragments
• amyloid beta-protein (1-42)
• amyloid beta-protein (25-35)

Topics

• Alleles
• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid beta-Peptides (biosynthesis, metabolism, toxicity)
• Amyloid beta-Protein Precursor (metabolism)
• Apoptosis (genetics)
• Cell Line, Tumor
• Genetic Predisposition to Disease (genetics)
• Genetic Variation
• Hemochromatosis Protein
• Histocompatibility Antigens Class I (genetics)
• Humans
• Membrane Proteins (genetics)
• Mitochondria (metabolism, pathology)
• Neurons (drug effects, metabolism)
• Peptide Fragments (biosynthesis, metabolism, toxicity)