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The purpose of this study was to determine the level of 8-oxo-2'-deoxyguanosine (8-oxo2dG) and expression of three isoforms of 8-oxoguanine glycosylase 1 (OGG1), OGG1-1a, 1b, and 1c, and OGG1 protein and Ser326Cys and Arg46Gln polymorphisms of the OGG1 gene, in peripheral blood lymphocytes of patients with Alzheimer's disease (AD) and healthy controls. The study was performed in 41 AD patients and 51 healthy subjects. The level of 8-oxo2dG was determined by high performance liquid chromatography/electrochemical; expression of OGG1-1a, 1b, and 1c by real-time quantitative polymerase chain reaction; and OGG1 protein by Western blotting. The polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to analyze the Ser326Cys and Arg46Gln polymorphisms. It was found that AD patients and controls have three isoforms, OGG1-1a, 1b, and 1c. The OGG1-1c isoform seems to be associated with early stage of AD, while an increase in the expression of the OGG1-1b isoform and levels of OGG1 protein appears to be similarly related to the progression of AD. All of the studied OGG1 isoforms show a decreased expression in advanced AD. The CG Ser326Cys genotype seems to have a tendency to decrease 8-oxo2dG via control of repair mechanisms. The Arg46Gln polymorphism is not associated with the pathogenesis of AD. It appears that the OGG1-1a, 1b, and 1c isoforms are involved in the pathogenesis of AD.

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are accompanied by increased levels of 8-oxo-2'-deoxyguanosine (8-oxo2dG) and alterations in levels of homocysteine (Hcy), methionine (Met), and cysteine (Cys). Hcy may undergo remethylation due to involvement of MTHFR, MTR and MTHFD1 proteins. Present studies are aimed at determination of 8-oxo2dG, Hcy, Met, and Cys in AD and PD patients as well as in control groups, using HPLC/EC/UV, as well as estimation, by restriction analysis, frequency of following gene polymorphisms: MTHFR (C677T, A1298C, G1793A), MTHFD1 (G1958A), and MTR (A2756G). In AD there were significant differences of the levels of only Cys (GG, MTHFR, G1793A) and Met/Hcy (AA, MTHFD1, G1958A) whereas in PD there were more significant differences of the levels of thiols: Hcy [MTHFR: CT (C677T) and GG (G1793A); MTR, AG (A2756G)], Met [MTR, AA (A2756G)], Cys [MTR, AG (A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T) and AA (A1298C), and GG (G1793A); MTHFD1 AA(G1958A); MTR AA(A2756G)]. Significant differences in the levels of Cys/Hcy, MTHFD1 GA (G1958) were varied between AD and PD groups. The results indicate that of the enzymes studied only polymorphisms of folate-dependent enzyme MTHFD1 have pointed to significant differences in intensity of turnover of circulating thiols between AD and PD patients.

The study aimed at the analysis of polymorphisms in the gene coding for the nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) and the evaluation of the extent of the oxidative damage to DNA (8-oxo2dG), as well as the level of proteins participating in DNA repair (p53, PARP) and DNA degradation (Bax:Bcl-2, 85-kDa fragment) in the peripheral blood lymphocytes of the patients suffering from Alzheimer's disease (AD) and in the healthy individuals of the control group. In the AD patients the increased levels of oxidized guanine were demonstrated in DNA, accompanied by the elevated expression of p53, Bax, PARP, and of a 85-kDa protein subunit as well as an augmented ratio of Bax:Bcl-2. Also, the level of Bcl-2 protein was decreased. In the AD patients with the CHRNA4 polymorphisms the highest level of 8-oxo2dG and of proteins involved in DNA repair were documented in patients with polymorphisms in exon 5, in contrast to the patients with polymorphisms in intron 5. In the former patients, levels of pro- and antiapoptotic proteins remained at the same level. Both CHRNA4 polymorphisms and the extent of dementia seem to affect the levels of DNA oxidative damage as well as to activate factors that participate in the DNA degradation and its repair.

This article presents an abstract of the research paper "Oxidative Damage to DNA and the Level of Apoptotic Proteins in Lymphocytes From Alzheimer's Disease Patients," which was discussed in the 13th Conference of the Polish Association of Neuropathologist. According to the paper, oxidative stress is an important factor in the pathogenic cascade of Alzheimer's disease (AD) and in degenerative neuronal death and disease progression. In the brains of AD patients, the level of reactive forms of oxygen (RFO) increases. RFO induces DNA oxidation products of purines.

The aging induces free radicals leading to DNA damage (8-oxo-2′-deoxyguanosine, 8-oxo2dG). DNA injury causes increased expression of p53 gene and p53 protein. Levels of 8-oxo2dG (HPLC), p53 mRNA (PCR) and p53 protein (Western blot) were estimated in gray matter (GM), white matter (WM), cerebellum (C) and medulla oblongata (MO) of control, 12- and 24-month-old rats. The level of 8-oxo2dG increased with age in C (P < 0.05 in 12-month-old and P < 0.01 in 24-month-old rats) and MO. In 12-month-old animals the level of 8-oxo2dG in GM and WM was higher than in controls. In 12-month-old animals p53 gene expression decreased while amounts of p53 protein increased, depending on the oxidative DNA damage. In 24-month-old rats, expression of p53 increased in all structures (P ≤ 0.05) while p53 protein showed decreased levels in most of structures of central nervous system (WM, C, MO). Aging leads to increased 8-oxo2dG and augmented p53 gene expression, accompanied by a lowered expression of p53 protein. [ABSTRACT FROM AUTHOR]