Association of <i>HFE</i> mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with <i>APOE</i>

Pulliam, Joseph F.; Jennings, C. Darrell; Kryscio, Richard J.; Davis, Daron G.; Wilson, Dianne; Montine, Thomas J.; Schmitt, Frederick A.; Markesbery, William R.

doi:10.1002/ajmg.b.10069

Cited by 84 publications

(55 citation statements)

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“…However, it has been shown that hemochromatosis mutations are associated with increased oxidative stress and progression of disease pathology [76] . [78] .…”

Section: Metal Accumulationmentioning

confidence: 99%

“…In addition, Cu + can donate two electrons to oxygen, generating H 2 O 2 [72,73] , and further producing hydroxyl radicals (Fenton-type reaction) [74] . Iron accumulation is also present in cells associated with neuritic plaques in AD [75] , which results in the increase of oxidative stress.However, it has been shown that hemochromatosis mutations are associated with increased oxidative stress and progression of disease pathology [76] . [78] .…”

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confidence: 99%

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Oxidative stress in Alzheimer’s disease

2014

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Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, infl ammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.Keywords: Alzheimer's disease; oxidative stress; β-amyloid; tau; metals; antioxidants ·Review· IntroductionThe human brain, although it constitutes only 2% of the body weight, consumes ~20% of the oxygen supplied by the respiratory system [1] . The high energy-consumption of the brain means that it is more susceptible to oxidative stress than any other organ. As the basic functional unit of the brain, the neuron is particularly vulnerable to oxidative damage because it has a higher metabolic rate than other cells [2] . The oxidation of lipids, proteins, and nucleic acids in neurons is a common pathological feature of Alzheimer's disease (AD) [3] . Neurons contain a large amount of polyunsaturated fatty acids (PUFAs) that can interact with reactive oxygen species (ROS), leading to a selfpropagating cascade of lipid peroxidation and molecular destruction [4] . Furthermore, neurons contain low levels of glutathione, an essential antioxidant for eliminating free radicals [5] . Therefore, neurons are highly susceptible to oxidative stress.An increased oxidative burden has been reported in the brains of non-demented elderly and/or sporadic AD patients [6,7] . Increased levels of oxidative stress biomarkers in the blood reflect such stress in the brain [8,9] . Currently, many blood markers of oxidative stress have been identified in AD patients or related animal models, including protein carbonyls and 3-nitrotyrosine [10,11] , , malondialdehyde (MDA) [12] , 4-hydroxynonenal (4-HNE), and F2-isoprostanes (F2-IsoPs) [13][14][15][16] . Apart from the intracellular accumulation of free radicals, changes in the activities or expressions of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have also been described in both the central nervous system and peripheral tissues of AD patients [14,17] . Thus, oxidative stress is an important pathological feature in AD.However, how and where the oxidative stress originates in AD are open questions. Research has suggested that mitochondrial dysfunction [12,18,19] , metal accumulation [12,20,21] , hyperphosphorylated tau [22,23] , inflammation [24,25] , and β-amyloid (Aβ) accumulation [12,19] are the basic mechanisms underlying the induction of oxidative stress. Deficiency or destruction of components of the antioxidant system such as SOD in the mi...

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“…However, it has been shown that hemochromatosis mutations are associated with increased oxidative stress and progression of disease pathology [76] . [78] .…”

Section: Metal Accumulationmentioning

confidence: 99%

mentioning

confidence: 99%

Oxidative stress in Alzheimer’s disease

2014

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“…Iron overload has been postulated to play a role in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease [12], Alzheimer's disease [13,14], and amyotrophic lateral sclerosis [15]. This suggests that the central nervous system is susceptible to iron-induced oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

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SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

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“…an endocrinological recruitment to improve the effectiveness of genotyping, and perhaps prevent morbimortality (20)(21)(22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department

Vantyghem¹,

Fajardy²,

Dhondt³

et al. 2006

eur j endocrinol

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Objective: The aim of this study was to describe HFE genotype in a population of patients with altered iron markers recruited in an Endocrinology Department and to define the possible phenotypegenotype relationships. Methods: A total of 156 patients with high serum ferritin concentrations (O300 ng/ml) or transferrin saturation (O45%) (I group), and a control group of 106 healthy subjects (C group) underwent HFE genotyping (classical C282Y and H63D mutations). We also examined the main genetic features of subgroups in I according to the presence (D) or the absence (ND) of diabetes. Results: (1) The genotypes were significantly different in the I and C groups (P!0.001), with an increased frequency of major 282Y allele in the I group (35% vs 7.5%), but not of minor 63D allele (17 vs 18.5%). (2) The genotype of D and ND groups also differed (P!0.0001), with a lower frequency of C282 heterozygosity (P!0.0001) in the D group, and a higher prevalence of H63D heterozygosity in the D vs ND groups (P!0.01). (3) The phenotypic comparison of D and ND groups also showed a higher mean body mass index, age, and serum ferritin concentration, as well as an increased proportion of males with increased liver enzymes in the D group. Conclusion: This population harboring abnormal iron markers had a different HFE genotype and a higher 282Y allele frequency than the control population. This suggests that blood iron markers could be checked in etiological investigations of metabolic disturbances to identify patients who should undergo genotyping, since approximately 20% were diagnosed with C282Y homozygosity.European Journal of Endocrinology 154 835-841

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Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer's disease and correlation with APOE

Cited by 84 publications

References 36 publications

Oxidative stress in Alzheimer’s disease

Oxidative stress in Alzheimer’s disease

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Phenotype and HFE genotype in a population with abnormal iron markers recruited from an Endocrinology Department

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