Expression of 8-oxoguanine DNA glycosylase 1 (OGG1) and the level of p53 and TNF-αlpha proteins in peripheral lymphocytes of patients with Alzheimer's disease.

The aim of the study was to determine the extent of oxidative DNA damage (levels of 8-oxo2dG) and expression of OGG1 and p53 and TNF-α proteins in lymphocytes of Alzheimer's disease (AD) patients and a control group. The studies were conducted on 41 patients with AD, including 25 women and 16 men aged 34-84 years. The control group included 51 individuals, 20 women and 31 men aged 22-83 years. The level of 8-oxo2dG was determined using HPLC/EC/UV, and the level of OGG1 and p53 and TNF-α proteins was determined with the Western blot method. The results showed that both proteins participating in DNA repair (OGG1, p53) and the inflammatory protein TNF-α are involved in pathogenesis of neurodegenerative diseases. It also seems that a specific system for DNA repair (OGG1) may contribute to downregulation of the inflammatory factor (TNF-α) level, especially in the early stages of dementia. Moreover, the results showed that p53 protein can fulfil its function in DNA damage repair only in early stages of dementia. It is possible that OGG1 and p53 and TNF-α proteins together or separately may be involved in pathogenesis of AD by repair of oxidative DNA damage and/or apoptosis.

[Analysis of changes in peripheral and central nervous system in irregularly treated adult patients with primary congenital hypothyroidism]. / Analiza zmian w obwodowym i osrodkowym ukladzie nerwowym u niesystematycznie leczonych doroslych chorych na pierwotna wrodzona niedoczynnosc tarczycy.

UNLABELLED: Lack of thyroid hormones in the womb and the first years of life causes changes in the nervous system and mental retardation. The aim of the study was to assess changes in peripheral and central nervous system in 29 adult patients with primary congenital hypothyroidism (PCH) depending on the cause of the disease and systematic treatment of L-thyroxine. MATERIAL AND METHODS: The analysis was performed in 29 adult patients with PCH (16 women, 13 men) on the basis of the results of neurological examination, EEG, SPECT (Computer tomography single photon emission) of the brain. RESULTS: Changes in the nervous system were found in 72% of respondents. Patients who had implemented replacement therapy L-thyroxine after completing 12 months of age showed the most neurological disorders. There were variations in the cranial nerves III, IX, IV and VI. In 34% of respondents revealed paraneoplastic cerebellar symptoms, while the pyramid, and extrapyramidal symptoms in 10% and 3% of the people. EEG showed changes in brain bioelectrical activity in the entire study group. In the 83% found a significant asymmetry in regional cerebral blood flow (rCBF). Hypoperfusion outbreak occurred mainly in the stands and leading occipital. The relationship between time of initiation of treatment, and the presence of a systematic change in the nervous system was inversely proportional. In turn, analyzing the causes of most PCH deviations were found in the nervous system in patients with athyreosis. Brain SPECT study in these patients confirmed the organic changes in brain development. CONCLUSIONS. The presence and extent of changes in peripheral and central nervous system depends on the cause PCH, pending the implementation of L-thyroxine treatment and systematic. Studies of brain SPECT and EEG confirmed the existence of developmental changes of the brain in patients with PCH.

[The incidence of the thyroid microsomal autoantibodies in Alzheimer disease]. / Wystepowanie autoprzeiwcial przeciw frakcji mikrosomalnej tarczycy w chorobie Alzheimare.

BACKGROUND: Alzheimer disease is associated with degeneration of brain by deposition of beta-A4 amyloid protein. Above protein is a product of amyloid protein precursor proteolysis. This protein is coded by chromosom 21 together with histocompatibility antigens on surface of thyroid follicle. Until now the study suggest coexistence of autoimmune thyroid disease and Alzheimer disease. The aim of the study was evaluation of thyroid autoantibodies in Alzheimer disease. MATERIAL AND METHODS: Study were performed in 34 Alzheimer disease patients. Sera of control subjects were obtained from 20 patients with vascular dementia. Incidence of thyroid autoantibodies was assessed by polyacrylamide electrophoresis gel and western-blotting. Thyroid microsomes were obtained from human thyroid tissues by ultracentrifugation and solubilization in 1% desoxycholic acid. RESULTS: In 21 sera from 34 we detected autoantibodies against thyroid microsomal antigens reacting with 91 kDa antigen. 16 sera were reacting with 97 kDa, 13 sera with 55 kDa, and 7 sera with 67 kDa proteins. CONCLUSIONS: In sera of Alzheimer disease patients autoantibodies against thyroid microsomal antigens can be frequently detected. The most frequent are antibodies against 91 kDa. It is important to note that Alzheimer disease patients should be screen for thyroid hormones.

Expression and polymorphisms of gene 8-oxoguanine glycosylase 1 and the level of oxidative DNA damage in peripheral blood lymphocytes of patients with Alzheimer's disease.

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.

Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases.

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.

Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer's disease.

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.

Amyloid precursor protein gene analysis in familial Alzheimer's disease cases: a lack of mutations in exons 16 and 17.

The beta-amyloid precursor protein (APP) gene (on chromosome 21), Presenilin 1 (PS1) gene (on chromosome 14) and Presenilin 2 (PS2) gene (on chromosome 1) are responsible for autosomal dominant early-onset Alzheimer's disease (EOAD). Missense mutations in these genes cause abnormal APP processing with subsequent overproduction of amyloidogenic and toxic A beta (42 peptide. A mutational analysis of APP, PS1, and PS2 genes can be used for both symptomatic and presymptomatic genetic testing and counselling in familial Alzheimer's disease (FAD). To contribute to our knowledge on genetic background of Alzheimer's disease in Poland, we screened APP mutations in a sample of familial EOAD cases from Poznan region. We did not find pathogenic mutations within exons 16 and 17 of the APP gene. Our study confirmed that APP gene mutations account only for a very small portion of FAD.

Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease.

Mutations in Presenilin 1 (PS1) and Presenilin 2 (PS2) genes account for up to 50% of familial early-onset Alzheimer's disease (EOAD). In order to assess the genetic contribution of the PS genes in a series of Polish patients, we performed a mutational analysis in 6 autosomal dominant (ADEOAD), 8 familial and 41 sporadic EOAD cases from Poznan region. Three missense mutations in the PS1 gene (Ala246Glu in exon 7, Pro267Leu in exon 8, and Leu424Arg in exon 12) were found in patients from families with ADEOAD. In addition, the Glu318Gly noncausative polymorphism in exon 9 was detected in two unrelated sporadic EOAD cases. The variation was also absent from other 53 patients and 48 controls. Therefore, we could not confirm the previous suggestion that the Glu318Gly substitution may be a risk factor for AD.

Genetic study of familial cases of Alzheimer's disease.

A small number (1-5%) of Alzheimer's disease (AD) cases associated with the early-onset form of the disease (EOAD) appears to be transmitted as a pure genetic, autosomal dominant trait. To date, three genes responsible for familial EOAD have been identified in the human genome: amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutations in these genes account for a significant fraction (18 to 50%) of familial cases of early onset AD. The mutations affect APP processing causing increased production of the toxic Abeta42 peptide. According to the "amyloid cascade hypothesis", aggregation of the Abeta42 peptide in brain is a primary event in AD pathogenesis. In our study of twenty AD patients with a positive family history of dementia, 15% (3 of 20) of the cases could be explained by coding sequence mutations in the PS1 gene. Although a frequency of PS1 mutations is less than 2% in the whole population of AD patients, their detection has a significant diagnostic value for both genetic counseling and treatment in families with AD.

Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznan region.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and personality changes. Pathological hallmarks of AD are: deposition of amyloid plaques and neurofibrillary tangles in the brain, accompanied by neuronal and synaptic loss. The genetic background of AD is heterogeneous and strongly depends on the form of the disease. In most of the families with early-onset AD (EOAD) (10% of the total population of patients), the disease segregates as an autosomal dominant fully penetrant trait. To date, some missense mutations in three genes encoding the amyloid precursor protein, presenilin 1 (PS1) and 2 (PS2) have been found to cause familial EOAD. We screened for mutations in the presenilin genes in a sample of 55 patients with familial or sporadic form of EOAD from the Poznan region. We found 4 missense mutations in the PS1 gene: A246E in exon 7, P267L in exon 8, E318G in exon 9, and L424R in exon 12 among 5 unrelated patients. The frequency of PS1 mutations was 11% (5 of 55) in the whole sample of the patients with EOAD or 50% (3 of 6) if the analysis was restricted to familial cases with a positive history of dementia in the patient's family.

[Paroxysmal focal dystonia as the initial manifestation of multiple sclerosis: case report]. / Napadowa dystonia ogniskowa jako poczatkowy objaw stwardnienia rozsianego--opis przypadku.

Paroxysmal phenomena such as dystonia in multiple sclerosis (MS) have approximate incidence ranged between 3.8%-17%. These symptoms in MS may represent transient phenomena related to inflammation in acute plaques and probably are secondary to irritation of demyelinated axons by lymphokines. Paroxysmal dystonia can occur at any time during the course of MS, but usually is the initial manifestation of demyelinating disease. We present the case of 42-year old woman with paroxysmal dystonia as the initial symptom of MS. Further MRI studies and CSF analysis revealed findings typical for MS. Patient's neurological status improved temporary after methyloprednisolone therapy. Paroxysmal dystonia may be related to ectopic impulses, release of inflammatory soluble factors, dysfunction of ion channels and accumulation of extra-cellular potassium. Paroxysmal dystonia often causes diagnostic difficulties, especially when it is the only or the initial symptom of the disease. It requires differential diagnosis with other diseases of central nervous system such as epilepsy and neurodegenerative or inflammation pathology.