ReviewBiomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment
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
References (350)
- et al.
DNA strand breaks in Alzheimer's disease
Brain Res.
(1999) - et al.
Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and neurofurans
Methods Enzymol.
(2007) - et al.
Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey
Clin. Biochem.
(2007) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) Free radicals and aging
Trends Neurosci.
(2004)- et al.
Accumulation of lipid peroxidation-derived DNA lesions: potential lead markers for chemoprevention of inflammation-driven malignancies
Mutat. Res.
(2005) - et al.
Cell cycle regulation of neuronal apoptosis in development and disease
Prog. Neurobiol.
(2004) - et al.
Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography-tandem mass spectrometry
J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci.
(2003) - et al.
Hypothetical role of RNA damage avoidance in preventing human disease
Mutat. Res.
(2005) - et al.
Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment
Neurobiol. Aging
(2009)
Proteomics: a new approach to investigate oxidative stress in Alzheimer's disease brain
Brain Res.
Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease
Neurobiol. Dis.
Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment
Neurosci. Lett.
Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease
Brain Res.
Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part I. Creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1
Free Radic. Biol. Med.
Peripheral antioxidant enzyme activities and selenium in elderly subjects and in dementia of Alzheimer's type—place of the extracellular glutathione peroxidase
Free Radic. Biol. Med.
Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients
Free Radic. Biol. Med.
Effects of oxidative and nitrosative stress in brain on p53 proapoptotic protein in amnestic mild cognitive impairment and Alzheimer disease
Free Radic. Biol. Med.
Vitamin E levels, cognitive impairment and dementia in older persons: the InCHIANTI study
Neurobiol. Aging
Identification of oxidized plasma proteins in Alzheimer's disease
Biochem. Biophys. Res. Commun.
Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases
J. Biol. Chem.
Molecular inflammation: underpinnings of aging and age-related diseases
Ageing Res. Rev.
Production of superoxide anions by a CNS macrophage, the microglia
FEBS Lett.
Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer's disease
Life Sci.
Oxidized proteins in Alzheimer's plasma
Biochem. Biophys. Res. Commun.
Isoprostanes as a biomarker of lipid peroxidation in humans: physiology, pharmacology and clinical implications
Trends Pharmacol. Sci.
Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits
J. Biol. Chem.
Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment
Neurobiol. Aging
Proteasomes and proteasome inhibition in the central nervous system
Free Radic. Biol. Med.
Free radical-induced damage to DNA: mechanisms and measurement
Free Radic. Biol. Med.
O6-methylguanine-DNA methyltransferase in lymphocytes of the elderly with and without Alzheimer's disease
Mutat. Res.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
Plasma levels of 8-epiPGF2alpha, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer's disease
Free Radic. Biol. Med.
DNA repair in neurons: so if they don’t divide what's to repair?
Mutat. Res.
Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease
Neurobiol. Aging
Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein
FEBS Lett.
Common mechanisms of amyloid oligomer pathogenesis in degenerative disease
Neurobiol. Aging
Remarkable increase in the concentration of 8-hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer's disease
J. Neurosci. Res.
No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease
Mov. Disord.
Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment
J. Neurochem.
Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders
Dement. Geriatr. Cogn. Disord.
Oxidants, antioxidants, and the degenerative diseases of aging
Proc. Natl. Acad. Sci. U.S.A.
Oxidative stress in neurodegeneration: cause or consequence?
Nat. Med.
DNA damage and apoptosis in Alzheimer's disease: colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay
J. Neurosci.
Oxidation-dependent changes in the stability and permeability of lipid bilayers
Antioxid. Redox Signal.
Revised criteria for mild cognitive impairment: validation within a longitudinal population study
Dement. Geriatr. Cogn. Disord.
Evidence of an oxidative challenge in the Alzheimer's brain
Neurochem. Res.
Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease
J. Alzheimers Dis.
Neurodegenerative diseases and oxidative stress
Nat. Rev. Drug Discov.
The contribution of the DNA damage response to neuronal viability
Antioxid. Redox Signal.
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