Searching for the role and the most suitable biomarkers of oxidative stress in Alzheimer's disease and in other neurodegenerative diseases

doi:10.1016/j.neurobiolaging.2004.10.002

Neurobiology of Aging

Volume 26, Issue 5, May 2005, Pages 587-595

https://doi.org/10.1016/j.neurobiolaging.2004.10.002 Get rights and content

Abstract

The contribution of oxidative stress to neurodegeneration is not peculiar of a specific neurodegenerative disease, oxidative stress has been found implicated in a number of neurodegenerative disorders among which Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS). Even increasing are studies dealing with the search for peripheral biomarkers of oxidative stress in biological fluids or even in peripheral tissues themselves such as fibroblasts or blood cells. The application of the modified version of the comet assay for the detection of oxidised purines and pyrimidines in peripheral blood leukocytes results particularly useful if the study requires repeated blood drawn from the same individual, for instance if a clinical trial is performed with a preventive therapy. Likely damage occurs to every category of biological macromolecules and we consider, in the context of neurodegenerative diseases, particularly critical the proteic level. The identification of subjects at risk to develop AD or with pre-pathogenic conditions, the possibility to use “a battery of assays” for the detection of oxidative damage at peripheral level, together with recent advances in brain imaging, will allow to better address studies aimed not only to therapeutic purposes but also mainly to primary prevention.

Section snippets

Oxidative stress in Alzheimer's disease and in other neurodegenerative diseases

Starting from the last but one sentence of our article [60], where we stated that the peripheral marker of oxidative stress we assessed cannot be considered peculiar only for Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) individuals, as Praticò in his commentary observed [75], we would like to enlarge our view to the broader field of neurodegenerative diseases. Recently, we published a review summarising the last findings in the field of carcinogenesis and neurodegenerative

Peripheral biomarkers for the detection of oxidative stress

It is to our opinion of extreme importance to have demonstrated that significant biological changes related to a condition of oxidative stress have been found not only in brain tissue but also in peripheral tissues of AD individuals. Even increasing are studies dealing with the search for soluble peripheral biomarkers of oxidative stress in biological fluids, mainly cerebrospinal fluid (CSF) but also peripheral blood (PB) (serum/plasma) or urines or even in peripheral tissues themselves such as

Use of different peripheral cell types for the detection of oxidative damage

We agree with the comments of Gibson and Haung [33] on the fact that fibroblasts are an excellent substrate to perform mechanistic studies, since circulating leukocytes are more prone to be susceptible to confounding factors linked to diet or drugs. Also, primary cultures of human olfactory neurons from AD patients proved to be an interesting model for studying oxidative damage [29]. However, the comet assay in our hand (and in most laboratories who perform this assay) was primarily set up in

Biomarkers of DNA damage

The comet assay or single cell gel electrophoresis (SCGE) is a rapid, simple and sensitive device able, in its classical alkaline version, to quantify genomic damage at the individual cell level and specifically to detect DNA strand breaks. In the last years, its use has become a tool even more employed in human biomonitoring studies having also increasing applications in the assessment of DNA damage in subjects affected by various pathological conditions [1], [38] and in the investigation of

Oxidative stress and the functionality of the proteasome

If, as it results from many literature evidences, oxidative stress is a common feature of neurodegenerative diseases, what can be the consequences at molecular level? We found that either in AD, MCI or PD, there is an increase in oxidatively-damaged DNA at peripheral level, but likely damage occurs to every category of biological macromolecule prior to lesion formation and we consider in the context of neurodegenerative diseases, particularly critical the proteic level. As reviewed by

Individuals at risk to develop AD as human model

To better address basic, therapeutic and mainly preventive approaches, studying pre-symptomatic subjects or individuals more prone to develop AD represents the best tool. For this purposes, as Gibson and Haung [33] suggest, patients with predisposition to develop AD can be a good model to verify the onset of biological changes due to oxidative stress. Examples for that are MCI subjects but also pre-synthomatic individuals belonging to families with FAD and carrying the causative mutation in APP

Antioxidant treatments for neurodegenerative diseases

The intense investigations on the mechanisms by which neurons die, and the recent findings on the involvement of oxidative stress in many neurodegenerative diseases, have led to the idea that the therapeutic use of antioxidants could be of help in aging and neurodegenerative diseases. Novel therapeutic neuroprotective strategies support the application of ROS scavengers, transition metal, like iron and copper, non-steroid anti-inflammatory drugs (NSAID), antiapoptotic drugs, and bio-energetic

Conclusions

We considered our study a contribution to the understanding of the molecular basis of AD because only if causative mechanisms of the disease are deeply understood, therapeutic but mainly preventive studies can be better addressed.

We are aware that for the scientific community and mainly for clinicians the search for valuable reliable peripheral markers of a disease can be of fundamental value. At least a set of biomarkers for the detection of oxidative stress (such as oxidative DNA damage but

References (105)

M.G. Andreassi et al.
Deoxyribonucleic acid damage in human lymphocytes after percutaneous transluminal coronary angioplasty
J Am Coll Cardiol
(2002)
F. Blandini et al.
Determination of hydroxyl free radical formation in human platelets using high-performance liquid chromatography with electrochemical detection
J Chromatogr B Biomed Sci Appl
(1999)
J. Blasiak et al.
DNA damage and repair in type 2 diabetes mellitus
Mutat Res
(2004)
J. Blasiak et al.
Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer
Mutat Res
(2004)
M. Bogdanov et al.
Increased oxidative damage to DNA in ALS patients
Free Radic Biol Med
(2000)
D. Bonnefont-Rousselot et al.
Blood oxidative stress in amyotrophic lateral sclerosis
J Neurol Sci
(2000)
C. Buhmann et al.
Plasma and CSF markers of oxidative stress are increased in Parkinson's disease and influenced by antiparkinsonian medication
Neurobiol Dis
(2004)
D.A. Butterfield et al.
Protein oxidation processes in aging brain
Adv Cell Aging Gerontol
(1997)
D.A. Butterfield
Proteomics: a new approach to investigate oxidative stress in Alzheimer's disease brain
Brain Res
(2004)
D.A. Butterfield et al.
Alzheimer's amyloid beta-peptide (1–42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide
Neurobiol Aging
(2004)

M.T. Carrì et al.

Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals

Brain Res Bull

(2003)

C. Cecchi et al.

Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients

Free Radic Biol Med

(2002)

J. Choi et al.

Identification of oxidized plasma proteins in Alzheimer's disease

Biochem Biophys Res Commun

(2002)

C.C. Conrad et al.

Oxidized proteins in Alzheimer's plasma

Biochem Biophys Res Commun

(2000)

F. Faust et al.

The use of the alkaline comet assay with lymphocytes in human biomonitoring studies

Mutat Res

(2004)

B. Friguet et al.

Inhibition of the multicatalytic proteinase (proteasome) by 4-hydroxy-2-nonenal cross-linked protein

FEBS Lett

(1997)

G.E. Gibson et al.

Differential alterations in antioxidant capacity in cells from Alzheimer patients

Biochim Biophys Acta

(2000)

G.E. Gibson et al.

Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme

Biochim Biophys Acta

(2002)

L. Giovannelli et al.

Measurement of DNA breaks and oxidative damage in polymorphonuclear and mononuclear white blood cells: a novel approach using the comet assay

Mutat Res

(2003)

M. Harangi et al.

Determination of DNA damage induced by oxidative stress in hyperlipidemic patients

Mutat Res

(2002)

N. Hattori et al.

Pathogenetic mechanisms of parkin in Parkinson's disease

Lancet

(2004)

Y. Ihara et al.

Superoxide dismutase and free radicals in sporadic amyotrophic lateral sclerosis: relationship to clinical data

J Neurol Sci

(1995)

S.V. Jovanovic et al.

Biomarkers of oxidative stress are significantly elevated in Down syndrome

Free Radic Biol Med

(1998)

E. Kan et al.

Assessment of DNA strand breakage by the alkaline comet assay in dialysis patients and the role of Vitamin E supplementation

Mutat Res

(2002)

J.N. Keller et al.

The proteasome in brain aging

Ageing Res Rev

(2002)

A. Kikuchi et al.

Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy

Neurobiol Dis

(2002)

W.E. Klunk

Blood and CSF biomarkers for AD revisited: what's new, what's good, and is this where we should be looking?

Neurobiol Aging

(2002)

D.K. Lahiri et al.

Lethal weapon: amyloid beta-peptide, role in the oxidative stress and neurodegeneration of Alzheimer's disease

Neurobiol Aging

(2004)

M.A. Lovell et al.

Markesbery WR. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease

Neurobiol Aging

(1997)

J. Luders et al.

The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome

J Biol Chem

(2000)

W.R. Markesbery

Oxidative stress hypothesis in Alzheimer's disease

Free Radic Biol Med

(1997)

L. Migliore et al.

Genetic and environmental factors in cancer and neurodegenerative diseases

Mutat Res

(2002)

M.J. Morillas et al.

Spontaneous and induced genetic damage in T lymphocyte subsets evaluated by the Comet assay

Mutat Res

(2002)

M. Mòrocz et al.

Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer's disease

Neurobiol Aging

(2002)

F. Nanjo et al.

Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical

Free Radic Biol Med

(1996)

P. Odetti et al.

Early glycoxidation damage in brains from Down's syndrome

Biochem Biophys Res Commun

(1998)

T.L. Perry et al.

Parkinson's disease: a disorder due to nigral glutathione deficiency?

Neurosci Lett

(1982)

G. Perry et al.

Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases?

Free Radic Biol Med

(2002)

A. Petronis

Alzheimer's disease and Down syndrome: from meiosis to dementia

Exp Neurol

(1999)

N. Salah et al.

Polyphenolic flavanols as scavengers of aqueous phase radicals and as chain-breaking antioxidants

Arch Biochem Biophys

(1995)

S. Sardas et al.

Assessment of DNA strand breakage by comet assay in diabetic patients and the role of antioxidant supplementation

Mutat Res

(2001)

M.L. Selley et al.

The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease

Neurobiol Aging

(2002)

J. Sierens et al.

Effect of phytoestrogen and antioxidant supplementation on oxidative DNA damage assessed using the comet assay

Mutat Res

(2001)

S. Song et al.

Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity

Mol Cell

(2003)

C.E. Teunissen et al.

Biochemical markers related to Alzheimer's dementia in serum and cerebrospinal fluid

Neurobiol Aging

(2002)

A. Theriault et al.

Tocotrienol. A review of its therapeutic potential

Clin Biochem

(1999)

E.E. Tuppo et al.

Sign of lipid peroxidation as mesured in the urine of patients with probable Alzheimer's disease

Brain Res Bull

(2001)

F.W. van Leeuwen

Neuropeptide research discloses part of the secrets of Alzheimer's disease neuropathogenesis: state of the art

Neurosci Lett

(2004)

S. Apostolski et al.

Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation

J Environ Pathol Toxicol Oncol

(1998)

O.I. Aruoma

Free radicals, oxidative stress, and antioxidants in human health and disease

J Am Chem Soc

(1998)

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Authors’ response to commentariesSearching for the role and the most suitable biomarkers of oxidative stress in Alzheimer's disease and in other neurodegenerative diseases

Abstract

Section snippets

Oxidative stress in Alzheimer's disease and in other neurodegenerative diseases

Peripheral biomarkers for the detection of oxidative stress

Use of different peripheral cell types for the detection of oxidative damage

Biomarkers of DNA damage

Oxidative stress and the functionality of the proteasome

Individuals at risk to develop AD as human model

Antioxidant treatments for neurodegenerative diseases

Conclusions

J Am Coll Cardiol

J Chromatogr B Biomed Sci Appl

Mutat Res

Mutat Res

Free Radic Biol Med

J Neurol Sci

Neurobiol Dis

Adv Cell Aging Gerontol

Brain Res

Neurobiol Aging

Brain Res Bull

Free Radic Biol Med

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Mutat Res

FEBS Lett

Biochim Biophys Acta

Biochim Biophys Acta

Mutat Res

Mutat Res

Lancet

J Neurol Sci

Free Radic Biol Med

Mutat Res

Ageing Res Rev

Neurobiol Dis

Neurobiol Aging

Neurobiol Aging

Neurobiol Aging

J Biol Chem

Free Radic Biol Med

Mutat Res

Mutat Res

Neurobiol Aging

Free Radic Biol Med

Biochem Biophys Res Commun

Neurosci Lett

Free Radic Biol Med

Exp Neurol

Arch Biochem Biophys

Mutat Res

Neurobiol Aging

Mutat Res

Mol Cell

Neurobiol Aging

Clin Biochem

Brain Res Bull

Neurosci Lett

Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation

J Environ Pathol Toxicol Oncol

Free radicals, oxidative stress, and antioxidants in human health and disease

J Am Chem Soc

Authors’ response to commentaries
Searching for the role and the most suitable biomarkers of oxidative stress in Alzheimer's disease and in other neurodegenerative diseases