Review Article
Epigenetics, oxidative stress, and Alzheimer disease

https://doi.org/10.1016/j.freeradbiomed.2009.02.006Get rights and content

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the β-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-β (Aβ). Increased Aβ levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.

Introduction

Epigenetics is a major mechanism that accommodates gene-expression changes in response to gene-environment interactions [1], [2]. Epigenetics refers to modifications in gene expression that are influenced by DNA methylation and/or chromatin structure, RNA editing, and RNA interference without any changes in DNA sequences [3]. DNA methylation and histone deacetylation are known to occur shortly after DNA synthesis and could be modified by diverse physiological or pathological factors, altering gene expression for the lifetime of the organism.

Section snippets

Epigenetics and mental disorders

Despite the fact that the bulk of the work in epigenetics has been developed in cancer research [4], there is recognition of epigenetic aberrations in mental illnesses, namely in fragile X disease and Rett syndrome [5], [6], [7]. Fragile X disease is associated with an expanded (> 250 copies) number of hypermethylated CGG repeats 5′ of the FMR1 gene that results in downregulation of the gene [5], [6]. Disease severity in fragile X is directly correlated with the extent of methylation in the 5′

Genetics and epigenetics of Alzheimer disease

Alzheimer disease (AD) is a gradual and irreversible progressive neurodegenerative disorder that results in dementia and death. AD pathology is characterized by senile plaques and neurofibrillary tangles, combined with massive neuronal loss, mainly in the hippocampus and association regions of the neocortex. The major constituents of senile plaques are 39- to 42-amino-acid peptides, snipped from a larger protein called β-amyloid precursor protein (APP) [16], [17], [18], [19], [20], [21]. Of

Role of oxidative stress in the etiology of AD

In addition to the established pathology of amyloid plaques and neurofibrillary tangles in the brain of AD sufferers, there is a growing body of evidence indicating changes in the redox status of AD brains. This is supported by findings of increased levels of oxidative damage markers in every major cellular macromolecule (proteins, lipids, and DNA) [34]. Also, alteration in the expression of antioxidant systems lends support to a role for free radical damage in AD pathology [35]. Owing to their

Scope of this review

This review focuses on epigenetics and explores the role of the environment in the promotion of AD pathogenesis through transcriptional dysregulation of genes associated with AD. In addition to the alteration in APP and Aβ metabolism, age-related accumulation of oxidative damage is also suspected to play a role in the pathogenesis of AD. Thus, any environmental agent that significantly alters the redox potential of the aging brain can theoretically promote AD pathology. Here we will explore the

Exposure to lead (Pb) and the developmental basis of AD

In a seminal study in 1989, David Barker and colleagues demonstrated an inverse relationship between birth weight and the incidence of cardiovascular disease. The Barker hypothesis, also known as the fetal or developmental basis of adult disease, states that many adult diseases might have a developmental origin [41], [42], [43], [44]. A large body of subsequent clinical and experimental data has supported this hypothesis and has shown that diseases of the cardiovascular system,

DNA methylation and the environment

The late onset responses to developmental exposure to Pb are probably unique to the nervous system and few other tissues. Because cells in most tissues turn over and proteins are in a continual cycle of synthesis and degradation, the molecular targets that would store and transmit this information would have to reside in the genome of terminally differentiated cells or cells that continually divide, passing along their genetic makeup. Furthermore, for the damage to persist on the structure of

Structure of the APP promoter and DNA methylation

The GC content of the APP promoter is estimated to be 72%, and the rate of CpG dinucleotides is five times that observed in other eukaryotic promoters, indicating that its expression would be subject to regulation by DNA methylation [78], [79], [80], [81], [82]. The Sp1 consensus sequence, 5′-GGGCGGG (lower strand, 5′-CCCGCCC), contains CG dinucleotides and is present in several places on the APP promoter. Few studies have examined methylcytosine levels on the APP promoter and the published

DNA methylation and oxidative stress

In CpG dinucleotides, the cytosine is the preferred base for DNA methylation, whereas the guanine is the site for oxidative damage. 8-OxodG is widely used as a biomarker of oxidative DNA damage. In the absence of exogenous DNA-damaging reagents, endogenously formed metabolic reactive oxygen species (ROS) are able to create 105 molecules of 8-oxodG in the cells per day [93]. Oxidative DNA damage is primarily repaired by the base excision pathway, and base excision repair is initiated by a DNA

Conclusion

The Pb-exposure model was used to test the hypothesis that the origins of AD occur early in life and that environmental exposure can determine future disease susceptibility. The effects of the original exposure would remain latent until an additional trigger or triggers affected the exposed organism. Such a model operates through the regulatory sequences of a gene and places the epigenotype center stage over genotype in the development of neuropsychiatric disorders. We refer to the model as the

Acknowledgments

We thank Dr. Riyaz Basha, Dr. Jinfang Wu, Hassan Siddiqi, and Bryan Maloney for performing some of the modeling experiments and Remi Dosunmu and Tarik Zawia for drawing cartoons and editing the manuscript. This research was supported by the National Institute of Environmental Health Sciences and the National Institute of Aging through grants (ES013022 and AG027246) awarded to N.H.Z. and (AG18379 and AG18884) to D.K.L. The research core facility at URI was funded (P20RR016457) by the National

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