Hydroxyoctadecadienoic acid and oxidatively modified peroxiredoxins in the blood of Alzheimer's disease patients and their potential as biomarkers☆
Introduction
The central nervous system is particularly vulnerable to oxidative damage and it has been suggested that oxidative stress might play an important role in the pathogenesis of Alzheimer's disease (AD) (reviewed in Halliwell, 2006, Montine et al., 2005a, Smith et al., 2002). In fact, many studies have demonstrated the increased levels of oxidation-associated metabolites and decline of antioxidant levels in the biological fluids of AD patients. For example, it has been observed in several studies that F2-isoprostanes, a group of lipid peroxidation products derived from arachidonic acid, are increased in AD patients (Markesbery et al., 2005, Montine et al., 2005b). Increased levels of 4-hydroxy-2-nonenal (HNE), another important lipid peroxidation product, have also been observed in AD patients (Butterfield et al., 2006b, VÖlkel et al., 2006, Williams et al., 2006). It was found that HNE promoted major conformational changes of tau (τ) associated with neurofibrillary tangles (Liu et al., 2005). Furthermore, 24S-hydroxycholesterol was also accepted as a relevant oxidation product (Bjorkhem et al., 2006, Heverin et al., 2004, Lutjohann et al., 2000, Reiss et al., 2004). In addition to lipids, the oxidation products of DNA (Migliore et al., 2005a) and proteins (Butterfield et al., 2006a) have also received attention.
Appropriate biomarkers are essential to understand the pathogenesis of AD and also facilitate the assessment of disease progression and response to therapeutics. Several biomarkers for AD have been examined and identified in the cerebrospinal fluid (CSF) and circulating plasma or serum (De Leon et al., 2006, Flirski and Sobow, 2005, Frank et al., 2003, Irizarry, 2004, Mielke and Lyketsos, 2006, Migliore et al., 2005b, Solfrizzi et al., 2006, Teunissen et al., 2003, Thal et al., 2006). It is imperative to identify biomarkers as indicators of disease progression in the differential diagnosis of dementia or to serve as surrogate markers of drug response in clinical trials.
Although there are accumulated data on peripheral biomarkers, especially lipid peroxidation products, in neuronal diseases, the results are conflicting. In the present study, we have measured the levels of oxidation products from linoleic acid, arachidonic acid, and cholesterol in the blood of AD and vascular dementia (VD) patients and compared the results with those of the control subjects. Further, we performed a proteome analysis of the erythrocytes of these patients and healthy controls to discover another biomarker for neurodegenerative diseases. We have recently proposed a method to measure the level of total hydroxyoctadecadienoic acid (tHODE) and 7-hydroxycholesterol (t7-OHCh) that may be used as biomarkers for lipid peroxidation in vivo (Yoshida and Niki, 2004). In this method, biological samples are reduced by sodium borohydride and then saponified by potassium hydroxide to convert hydroperoxides and ketones as well as hydroxides of both free and ester forms of linoleic acid and cholesterol to tHODE and t7-OHCh, respectively.
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Patients
AD (n = 39; male = 15, female = 24; age 76.2 ± 9.5 (mean ± S.D.)) and VD (n = 25; male = 8, female = 17; age 80.4 ± 9.2 (mean ± S.D.)) patients in the Aoisoranosato Geriatric Health Services Facility and the Arimakogen Hospital were recruited for this study. The diagnosis of AD was performed based on the criteria for probable AD (according to the generally accepted criteria prescribed by the DSM-IV). The diagnosis of VD was also based on the criteria prescribed by the DSM-IV. Use of medication among the AD and VD
Plasma and erythrocyte levels of tHODE
Blood samples of AD (n = 39) and VD (n = 25) patients and healthy controls (n = 24) were collected and analyzed immediately after they were drawn. Demographic information regarding the age, sex, smoking and drinking habits, and plasma lipid concentrations of the individuals has been summarized in Table 1. There was no significant difference in these factors among three groups in the present study. The plasma and erythrocyte levels of tHODE and t8-iso-PGF2α in AD and VD patients assessed independently
Discussion
The present study was performed to examine the oxidation products of lipids and peroxiredoxin as potential biomarkers for AD. Several biomarkers have been presented for AD, among them isoprostanes, 4-hydroxynonenal, malondialdehyde, oxysterols, 8-hydroxy-2′-deoxyguanosine, protein carbonyls, and nitrotyrosine are oxidative stress related measures (Flirski and Sobow, 2005, Frank et al., 2003, Halliwell, 2006, Montine et al., 2005b). Antioxidant levels and products have also been discussed (Foy
Conclusions
The results of the present study clearly indicate that the levels of tHODE in the plasma and erythrocytes and those of 8-iso-PGF2α in the plasma of AD patients are significantly higher than those of VD patients and controls and that the erythrocyte levels of oxPrx-2 and oxPrx-6 in AD and VD patients are higher than those of the controls. It should be noted that these oxidation products are by no means specific to AD. Oxidative stress might be involved in many other neurodegenerative diseases
Acknowledgements
We are grateful to Mieko Hayakawa, Yoko Habuchi, and Ruriko Inoue from the Human Stress Signal Research Center (HSSRC), the National Institute of Advanced Industrial Science and Technology (AIST), for their excellent and patient technical support. We also thank Dr. Yoshiyuki Sawai at the Ikeda Municipal Hospital for examining the clinical data.
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These authors contributed equally to this work.