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

Nootchanat Mairuae, Eric C. Hall, Poonlarp Cheepsunthorn, Sang Lee, James Connor

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 Aβ25-35 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, Aβ25-35 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 Aβ1-42 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.

Original languageEnglish (US)
Pages (from-to)3079-3089
Number of pages11
JournalJournal of Neuroscience Research
Volume88
Issue number14
DOIs
StatePublished - Nov 1 2010

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Amyloid
Mitochondria
Peptides
Genes
Alzheimer Disease
Apoptosis
Caspase 9
Amyloid beta-Protein Precursor
Cytochromes c
Neuroblastoma
Caspase 3
Cytosol
Epidemiologic Studies
Oxidative Stress
Homeostasis
Cell Death
Iron
Alleles

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

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title = "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 Aβ25-35 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, Aβ25-35 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 Aβ1-42 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.",
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The H63D HFE gene variant promotes activation of the intrinsic apoptotic pathway via mitochondria dysfunction following β-amyloid peptide exposure. / Mairuae, Nootchanat; Hall, Eric C.; Cheepsunthorn, Poonlarp; Lee, Sang; Connor, James.

In: Journal of Neuroscience Research, Vol. 88, No. 14, 01.11.2010, p. 3079-3089.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The H63D HFE gene variant promotes activation of the intrinsic apoptotic pathway via mitochondria dysfunction following β-amyloid peptide exposure

AU - Mairuae, Nootchanat

AU - Hall, Eric C.

AU - Cheepsunthorn, Poonlarp

AU - Lee, Sang

AU - Connor, James

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N2 - 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 Aβ25-35 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, Aβ25-35 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 Aβ1-42 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.

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