Elsevier

Ageing Research Reviews

Volume 8, Issue 4, October 2009, Pages 285-305
Ageing Research Reviews

Review
Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment

https://doi.org/10.1016/j.arr.2009.04.002Get rights and content

Abstract

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Aβ) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD.

Introduction

Alzheimer's disease (AD) is the most common type of dementia in the elderly, aging being the main risk factor. Due to the dramatic increase in the elderly population in developed countries, the already high prevalence of AD is expected to further rise to up to 13 million cases in USA and over 4 million cases in the EU in 2050 (Small et al., 1997, Hebert et al., 2003). Of the several age-related diseases, AD is a major socioeconomical and medical challenge because there is still no significant treatment. Therefore, much research has been undertaken in recent decades to decode the main pathophysiological changes responsible for AD development. The main biochemical pathways shown to be associated with the histophatological and clinical hallmarks of AD appear to be related to the production and metabolism of amyloid-beta (Aβ) fragments and neurofibrillary tangles (NFT) (Lambert et al., 1998, Deshpande et al., 2006, Cappai and Barnham, 2008). Furthermore, impaired bioenergetics (Beal, 2005), oxidative stress (Mariani et al., 2005, Valko et al., 2007) and inflammation (Chung et al., 2009) have been suggested as additional hallmarks. In addition to their individual role, biomarkers of oxidative and nitrosative stress in AD have been shown to be associated with altered bioenergetics and Aβ metabolism. For this reason, oxidative and nitrosative damage are generally accepted as a central process in AD pathophysiology. The aim of this work is to offer the reader an overview regarding the main results obtained in the field of oxidative/nitrosative stress in AD in humans. Furthermore, recent data concerning the role of oxidative/nitrosative stress in mild cognitive impairment (MCI) will also be assessed. In the following paragraphs, after a brief introduction on the theory of oxidative stress, we report the main results of studies on subjects with diagnosis of AD and MCI assessing the most widely investigated biomarkers of OS and NS in the brain, cerebrospinal fluid (CSF), blood and urine. We systematically searched the PubMed, National Library of Medicine database for English-language articles published from 1990 to January 2009 (last accessed on January 31, 2009). Furthermore, we found additional papers by performing a manual search of the reference lists of relevant retrieved articles.

Section snippets

Oxidative and nitrosative stress

Free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are molecules or molecular fragments containing one or more unpaired electrons in atomic or molecular orbitals, which characterises free radicals with high reactivity (Halliwell and Gutteridge, 1999). Exogenous agents (such as photochemical smog, ozone, pesticides, xenobiotics and ionizing radiation) and a variety of endogenous processes (for example, mitochondrial respiration, cytochrome P-450 detoxification

Oxidative and nitrosative damage in AD and MCI

AD is the most common neurodegenerative disorder worldwide. Neurophatologically, it is characterized by regionalized neuronal death, synaptic loss, accumulation of intraneuronal NFT and extracellular senile plaques (SP), and proliferation of reactive astrocytes in the entorhinal cortex, hippocampus, amygdala and association areas of frontal, temporal, parietal and occipital cortex. NFT are formed by intracellular deposits of paired helical filaments composed of hyperphosphorylated tau. SP can

Lipids

ROS can attack lipids and extract a hydrogen atom from a methylene carbon in their side chain. The greater the number of double bonds in the lipid molecule, the easier will be the removal of the hydrogen atom. This explains why the polyunsaturated fatty acid residues of phospholipids are very sensitive to ROS. Lipid peroxidation, which refers to the oxidative degradation of lipids, is one of the major outcomes of free radical-mediated injury. The peroxidation of lipids in plasmalemma or

Nucleic acids

Nucleic acids [nuclear DNA (nDNA), mitochondrial DNA (mtDNA), and RNA] are one of the cellular macromolecules damaged by free radicals. Mitochondrial DNA is more susceptible to OS/NS compared to nDNA (Barja, 2004). This is due to: (i) its lack of protective histones; (ii) its high information density, due to the absence of introns; (iii) its close proximity to the inner mitochondrial membrane, where ROS are generated; and (iv) the presence of limited repair mechanisms (Clayton et al., 1974,

Proteins

Within proteins, all amino acids can be attacked by ROS and RNS, but sulphur-containing and aromatic amino acids are the most susceptible (Stadtman and Levine, 2003). The oxidation of amino acids leads mainly to the formation of carbonyl derivates, while peroxynitrite (ONOO) can nitrate tyrosine groups of proteins and form the stable compound 3-nitrotyrosine. Another product of protein oxidation is dityrosine. Intracellular proteins might also be oxidatively modified via secondary mechanisms

Oxidative and nitrosative stress: cause or consequence in Alzheimer's disease?

The mechanisms responsible for the selective dysfunction and neuronal death in the AD brain remain unclear. Aging is the major risk factor for AD, and, since it has been largely proved that an elevation in oxidative/nitrosative damage is one of the most ubiquitous alterations observed in aging cells and tissues, it is likely that increased OS/NS contributes to the development of age-related disorders, such as AD. However, it has not been totally clarified whether the increased

Conclusions

While AD affects patients later in life, abundant evidence suggests the existence of a “preclinical” stage, commencing years before the clinical diagnosis, when an individual appears cognitively normal while he/she is undergoing extensive pathological changes in the brain. Biomarkers should serve as early diagnostic indicators or as markers of preclinical pathological change. Regarding the development and implementation of neuroprotective and disease-modifying therapies, the presence of robust

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