Oxidative damage in different degenerative dementia patients: Evaluation of the oxidative macromolecular damage and repair in Alzheimer's disease

Objective: Alzheimer?s disease (AD) is the most common neurodegenerative disorder of the elderly. It is characterized by its progressive clinical course, irreversable memory loss and cognitive disorders. Free radical-mediated oxidatively induced macromolecular damage plays a role in basic neurodegenerative mechanisms in Alzheimer?s disease. In this thesis, enyzmes which play a role in DNA repair mechanism and oxidative damage in macromolecular level (DNA, lipid, protein, carbohydrate) was studied in Alzheimer?s disease patients and healthy volunteers. In addition, matrix metalloproteinases (MMP2, MMP9) and tissue inhibitor of metalloproteinases (TIMP1, TIMP2) levels were investigated to see their effects on the radical damage and Alzheimer?s disease. Method: The study was carried out with periferal blood samples taken from 44 Alzheimer?s disease patients and 45 controls. DNA base damage was determined by isotope dilution GC-MS/MS. The mRNA expression levels of the two major DNA base excision repair enzymes, (NEIL1 and OGG1 glycosylases) were determined by RT-PCR. The levels of protein oxidation marker 3-Nitrotyrosine and MMP2, MMP9, TIMP1, TIMP2 were measured with ELISA. Malondialdehyde, one of the lipid peroxidation products and N?-carboxymethyllysine, an advanced glycation end product, levels were investigated with HPLC methods. Results: The level of FapyAde/106 bases, a lesion of base damage, were significantly higher in AD patients compared to those in control subjects (p=0,00). There were no statistically significant difference between AD patients and the control group in 8-OHGua/106 DNA bases, FapyGua/106 DNA bases, 5-OH-5-MeHyd/106 DNA bases and 5-OHCyt/106 DNA bases. The ThyGly, 5-OH-MeUra, 5-OH-Ura, 5,6-diOH-Ura damages were not detected neither in AD patients nor in the control group. The level of NEIL1 expression, one of the DNA repair enzymes was found to be 0,21 times more in AD patients compared with the control group. However; this increase was not statistically significant. OGG1 expression level was found to be 0,02 times less in patients than in control group. This decrease also was not significant. Where there were no statistically significant difference between AD patients and control group in 3-Nitrotyrosine and N?-carboxymethyllysine levels, the levels of malondialdehyde were significantly higher in AD patients compared to those in control subjects (p=0,000). The MMP2 and TIMP1 levels were significantly lower in the AD group than the control group (p= 0,000 and 0,003 respectively). On the other hand, there were no statistically significant difference between AD patients and control group in TIMP2 and MMP9 levels. Conclusion: This study is noteworthy since markers of oxidative macromolecular damage and expressions of DNA base excision repair enzymes has been studied extensively in AD patients. Oxidative macromolecular damage plays an important role in pathogenesis of Alzheimer?s disease. It is vey important to be able to detect which molecule is involved at which level of this process, in understanding the etiology and selection of treatment strategies for this disease. Furthermore, it is postulated that, gathering supporting evidence about the role of matrix metalloproteinases and their inhibitors in Aß peptids catabolism which is responsible for the Alzheimer?s disease pathogenesis will contribute to the literature. Key Words: Alzheimer?s disease, oxidative macromolecular damage, DNA repair, matrix metalloproteinases and tissue inhibitor of metalloproteinases