Alzheimer Disease: Janka Z

Zana M, Janka Z, Kálmán J. · Department of Psychiatry, Faculty of Medicine, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, 6 Semmelweis St, Szeged H-6725, Hungary. · Neurobiol Aging. · Pubmed #16624449 No free full text.

Abstract: Besides the genetic, biochemical and neuropathological analogies between Down's syndrome (DS) and Alzheimer's disease (AD), there is ample evidence of the involvement of oxidative stress (OS) in the pathogenesis of both disorders. The present paper reviews the publications on DS and AD in the past 10 years in light of the "gene dosage" and "two-hit" hypotheses, with regard to the alterations caused by OS in both the central nervous system and the periphery, and the main pipeline of antioxidant therapeutic strategies. OS occurs decades prior to the signature pathology and manifests as lipid, protein and DNA oxidation, and mitochondrial abnormalities. In clinical settings, the assessment of OS has traditionally been hampered by the use of assays that suffer from inherent problems related to specificity and/or sensitivity, which explains some of the conflicting results presented in this work. For DS, no scientifically proven diet or drug is yet available, and AD trials have not provided a satisfactory approach for the prevention of and therapy against OS, although most of them still need evidence-based confirmation. In the future, a balanced up-regulation of endogenous antioxidants, together with multiple exogenous antioxidant supplementation, may be expected to be one of the most promising treatment methods.

Kálmán J, Janka Z. · Szegedi Tudományegyetem, Pszichiátriai Klinika,Alzheimer-kór Kutatócsoport, Szeged. · Orv Hetil. · Pubmed #16255374 No free full text.

Abstract: Epidemiological, biochemical and pharmacological investigations provide increasing number of evidences that altered cholesterol metabolism contributes to the development of Alzheimer's disease. The objective of the present paper is to review existing information about the links of cholesterol and amyloid metabolism from the clinical and proposed etiological viewpoints of the most frequent dementing disorder in Hungary. Beta-amyloid peptide, the major component of the senile plaques in the Alzheimer's disease brains is the end product of the abnormal post-translational processing of its precursor, called amyloid precursor protein. The compartmentation of the amyloid precursor protein molecule within the cell membrane is regulated by the cholesterol content of the bilayers. The amyloid precursor protein molecule could be present either in-, or outside of the membrane rafts. Any kind of process, which alters the compartmentation preference of the amyloid precursor protein molecule, by transferring it to the membrane rafts, favours beta- and gamma-secretase cleavage, and should be recognised as an amyloidogenic process. If the blood-brain barrier is intact, the brain is not able to take up the lipoprotein particles responsible for the transport of cholesterol. Instead of the active uptake, neurons and glial cells synthetize cholesterol de novo, in a process, where the rate limiting enzyme is 3-hydroxy-3-methylglutaryl coenzyme A. On the other hand, the brain specific CYP46A1 enzyme is responsible for the degradation of cholesterol into a water soluble metabolite, called 24S-OH cholesterol. The decreased CYP46A1 activity in the brain of Alzheimer's disease patients raises membrane cholesterol levels, and as a consequence the amyloid precursor protein is shifted and deposited in the cholesterol rich lipid rafts leading to beta-amyloid peptide specific metabolism. Among the polymorphic variants of the apolipoprotein E gene, the E4 allele is considered as a major risk factor for Alzheimer's disease. The E4 allele carrier Alzheimer's disease probands have increased amyloid burden, decreased beta-amyloid peptide degradation, and less effective neuronal repair mechanisms. Even as early as age 30, patients with Niemann-Pick Type C disease show clinical and neuropathological signs of Alzheimer's disease. The point mutation of the protein responsible for the endosomal transport of cholesterol is considered as a major cause of the beta-amyloid peptide deposition in the brain of Niemann-Pick Type C patients. One of the most exciting recent discovery, that Niemann-Pick Type C disease could be recognised as a disease model for Alzheimer's disease. New, promising cholesterol metabolism related therapeutic approaches are discussed, but it is emphasized that the clinical evidences regarding their efficacy in Alzheimer's disease are still missing.

Galariotis V, Bódi N, Janka Z, Kálmán J. · University of Szeged, Department of Psychiatry, Szeged. · Ideggyogy Sz. · Pubmed #16173270 No free full text.

Abstract: This is a comprehensive paper in three parts covering history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The second part focuses on the differential diagnosis, genetics, molecular pathomechanism and pathology. The clinical diagnosis of frontotemporal dementia is based on the presence of a prominent disturbance of the executive function and of frontal lobe syndrome or a progressive aphasic syndrome without severe global cognitive impairment. Of other dementias, it is primarily Alzheimer's disease that it should be differentiated from, but other psychiatric disorders must also be ruled out. The disease has familial and sporadic forms. Recent identification of mutations in the gene encoding the microtubule-associated tau protein in the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has demonstrated that various tau dysfunctions can lead to neurodegeneration. Tau gene mutations have varied effects on the biology and function of the protein. This heterogeneous pathomechanism explains the wide range of clinical and neuropathological features observed in the FTDP-17. Tau and ubiquitin antibodies can be detected by sensitive immunohistochemical methods. The diagnosis of FTD should be based on neuropathological examination, and this is also the only method by which it can be definitely differentiated from other types of dementias.

Galariotis V, Bódi N, Janka Z, Kálmán J. · University of Szeged, Department of Psychiatry, Szeged. · Ideggyogy Sz. · Pubmed #16021963 No free full text.

Abstract: The authors report a comprehensive publication consisting of three parts going into the details of history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The first part of the present review deals with history, prevalence and clinical forms of FTD. The prototypical FTD with circumscribed atrophy was first described by Arnold Pick; Alois Alzheimer found the intraneural inclusions in the patients' brain. Later it was recognised that many patients had neither the atrophy nor the cellular changes, but genetic mutations have been identified. Frontotemporal dementia is a degenerative condition with unknown etiology in the frontal and anterior temporal lobes of the brain. It is a progressive neurobehavioral syndrome characterized by early decline in social interpersonal conduct, early impairment in the regulation of personal conduct, early emotional blunting, and early loss of insight. There are no reliable epidemiological studies on the prevalence of FTD, but it is well-accepted that FTD is a common cause for dementia before the age of 65 (it constitutes approximately five percent of all irreversible dementias). The nomenclature of the FTD has been confusing and continues to be. Three major clinical syndromes can be identified: 1 frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, 2. in semantic dementia (progressive fluent aphasia) there is a breakdown in the conceptual database which underlies language production and comprehension, 3. in progressive nonfluent aphasia the phonologic and syntactic components of language are affected. The authors report two cases, which can point to clinical symptoms and forms, and mention the problems of the differential diagnosis and therapy.

Kálmán J, Palotás A, Bódi N, Kincses TZ, Benedek G, Janka Z, Antal A. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary. · Brain Res Bull. · Pubmed #15862926 No free full text.

Abstract: Impaired neuronal energy metabolism, oxidative changes and microvascular abnormalities lead to altered lactate levels in Alzheimer's dementia. The aim of the present study was to assess whether intravenous sodium-lactate, a metabolic alternative and vasodilator that is thought to improve cognition, advances the cognitive performance of Alzheimer patients. Semantic categorization paradigm was used to present the electrophysiological correlates of natural scene categorization of Alzheimer patients before and after intravenous saline or sodium-lactate infusion. Mean amplitudes of event-related potentials (ERPs) were measured in two time windows before and after the treatments; two negative components (N1 between 150 and 250 ms and N2 between 400 and 600 ms) and one positive component (P2 between 250 and 400 ms) were identified. The negative components were more negative for the non-animal trials than for the animal trials while the positive component was similar for both categories. After the lactate treatment the amplitudes of the negative components became more negative mainly for the non-animal trials while the amplitude of the positive component turned more positive for the animal trials, however these changes were not significant. No changes have been observed after normal saline infusion. These results suggest that, contrary to its anticipated beneficial effects, sodium-lactate fails to significantly improve semantic categorization processes in Alzheimer's disease and this enhancement can be detected by recording ERPs. The effect of sodium-lactate to slightly improve semantic memory might be based on its positive effect on cardio- and cerebro-vascular function and neuronal metabolism.

Kálmán J, Palotás A, Kis G, Boda K, Túri P, Bari F, Domoki F, Dóda I, Argyelán M, Vincze G, Séra T, Csernay L, Janka Z, Pávics L. · Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary. · Eur J Neurosci. · Pubmed #15845094 No free full text.

Abstract: Bilateral temporoparietal hypoperfusion is a characteristic single photon emission computed tomography (SPECT) finding in Alzheimer's disease (AD). Lactate is a metabolic vasodilator and is known to provoke increased cerebral blood flow (CBF) in healthy adults. This work investigated whether lactate, which is present in high concentrations in AD cerebrospinal fluid, affects AD-specific perfusion abnormalities. Twenty mild-to-moderately demented AD probands participated in the self-controlled study. The regional CBF was examined utilizing (99m)Tc-HMPAO SPECT after sodium lactate infusion (0.5 M, 5 mL/kg body weight) and 0.9% NaCl infusion, one on each of two separate days. Despite the vasodilatator effects of sodium lactate, AD rCBF patterns did not show increase in temporo-parietal regions after its infusion. AD-specific bi-temporo-parietal reduction in CBF was accompanied by further hypoperfusion in the parieto-occipital areas after the sodium lactate infusion in seven patients, while no CBF changes were observed in the case of the remaining 13 probands. The pattern of the CBF abnormalities was not correlated with the apolipoprotein E genotype. The decreased vascular responsiveness to sodium lactate reflects disturbed vasoregulatory processes in AD and it is unlikely that lactate would have any relevance in the treatment of AD-related cerebral hypoperfusion, but could be used to improve the value of perfusion SPECT in the diagnosis of AD.

Kálmán J, Juhász A, Rimanóczy A, Palotás A, Palotás M, Szabó Z, Boda K, Márki-Zay J, Janka Z. · Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, Faculty of Medicine, University of Szeged, Semmelweis u.6, H-6725 Szeged, Hungary. · Dement Geriatr Cogn Disord. · Pubmed #12714797 No free full text.

Abstract: The objective of our study was to investigate whether an interaction exists between apolipoprotein E (APOE) genotype and the response of patients with Alzheimer's disease (AD) to selegiline treatment, and whether APOE genotype independently affects the rate of AD progression. A 48-week multicenter double-blind trial was undertaken on 43 patients with mild to moderate AD. Primary efficacy measures were the AD Assessment Scale (ADAS), an 11-item cognitive subscale of ADAS (ADAS-Cog/11) and the Mini Mental State Examination. Secondary outcome measures were Clinical Global Impression of severity and CGI of change scales. The therapeutic response to selegiline was not affected by APOE genotype. Our results revealed that the APOE4 allele carrier AD probands did not respond better to selegiline treatment than the APOE2-3 patients, i.e. APOE status did not influence the therapeutic outcome of selegiline treatment.

Mórocz M, Kálmán J, Juhász A, Sinkó I, McGlynn AP, Downes CS, Janka Z, Raskó I. · Biological Research Centre of Hungarian Academy of Sciences, Institute of Genetics, POB 521, H-6701, Szeged, Hungary. · Neurobiol Aging. · Pubmed #11755018 No free full text.

Abstract: Previous studies have provided evidence of the involvement of oxidative damage in the pathogenesis of Alzheimer's disease (AD). Although the role of oxidative stress in the aetiology of the disease is still not clear, the detection of an increased damage status in the cells of patients could have important therapeutic implications. The level of oxidative damage and repair capacity in peripheral lymphocytes of AD patients and of age-matched controls was determined by the Comet assay applied to freshly isolated blood samples with oxidative lesion-specific DNA repair endonucleases. This is less prone to errors arising from oxidative artifacts than chemical analytical methods; and is therefore a relatively reliable, as well as rapid method for assay of oxidative DNA damage in cells. Statistically significant elevations (P < 0.05) of oxidized purines were observed in nuclear DNA of peripheral lymphocytes from AD patients, compared to age matched control subjects, both at basal level and after oxidative stress induced by H(2)O(2.) AD patients also showed a diminished repair of H(2)O(2) -induced oxidized purines.

Kálmán J, Kudchodkar BJ, Murray K, McConathy WJ, Juhász A, Janka Z, Lacko AG. · Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107-2644, USA. · Dement Geriatr Cogn Disord. · Pubmed #10559565 No free full text.

Abstract: There is now sufficient evidence to suggest that cardiovascular pathology and altered lipid metabolism contribute to the development of late-onset Alzheimer's disease (AD). In the present study, 24 AD patients and 15 controls were assessed for cardiovascular risk based on serum lipid and lipid oxidation parameters. The AD patients appeared to have a more favorable cardiovascular risk profile than the controls based on high-density lipoprotein cholesterol (HDL-C) values. The levels of thiobarbituric-acid-reactive substances and the activity of the enzyme paraoxonase (PON) following copper oxidation indicate that female patients may have better protection against serum and perhaps tissue oxidants than males with AD. While the higher HDL-C values indicate lower cardiovascular risk, additional data on oxidized lipid parameters suggest a lower level of protection against serum oxidants in male AD probands. CopyrightCopyright 1999S.KargerAG,Basel

Pákáski M, Hugyecz M, Sántha P, Jancsó G, Bjelik A, Domokos A, Janka Z, Kálmán J. · Alzheimer's Disease Research Centre, Department of Psychiatry, University of Szeged, 6 Semmelweis, H-6725 Szeged, Hungary. · Neurochem Int. · Pubmed #19428784 No free full text.

Abstract: Besides being an important component of spices used worldwide, capsaicin has wide-ranging therapeutic potential as a hypolipidemic, antioxidant and anti-inflammatory agent. Accordingly, it is very important to investigate the long-term effect of capsaicin in the pathogenesis of Alzheimer's disease. In this study, the effects of capsaicin on the processing of amyloid precursor protein (APP) were investigated in an in vivo model. The APP mRNA and protein levels were examined in the brain cortices of control and capsaicin-treated rats. The protein kinase C (PKC) translocation state in the soluble and membrane-bound fractions and the levels of beta-secretase (BACE) were also evaluated. Capsaicin enhanced the level of membrane-bound APP 1.7-fold. The APP mRNA and PKC and BACE protein levels were unchanged after capsaicin treatment. These in vivo data indicate that capsaicin is able to interfere with the brain APP metabolism by promoting the amyloidogenic route. We suggest that PKC is not involved in the mechanism underlying the effects.

Hartai Z, Juhász A, Rimanóczy A, Janáky T, Donkó T, Dux L, Penke B, Tóth GK, Janka Z, Kálmán J. · Department of Psychiatry, University of Szeged, Szeged, Hungary. · Neurochem Int. · Pubmed #17023091 No free full text.

Abstract: Kynurenine aminotransferases (KAT I and KAT II) are responsible for the transamination of kynurenine (KYN) to form kynurenic acid (KYNA), an excitatory amino acid receptor antagonist. Since these members of the kynurenine pathway (KP) are proposed to be involved in the pathogenesis of Alzheimer's dementia (AD), the activities of these enzymes and the levels of these metabolites were measured in the plasma and red blood cells (RBCs) of AD and control subjects together with the inheritance of the apolipoprotein (APOE) epsilon4 allele. KYNA levels were significantly decreased both in the plasma and in the RBCs in AD, but the levels of KYN and the activities of KAT I and KAT II remained unchanged. No association has been found with the possession of the epsilon4 allele. These findings indicate an altered peripheral KP in AD regardless of the APOE status of the probands.

Bjelik A, Pákáski M, Bereczki E, Gonda S, Juhász A, Rimanóczy A, Zana M, Janka Z, Sántha M, Kálmán J. · Alzheimer's Disease Research Centre, Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, 6 Semmelweis u., Szeged H-6725, Hungary. · Neurochem Int. · Pubmed #16962684 No free full text.

Abstract: Many of the risk factors for cerebrovascular disease and atherosclerosis also increase the risk of Alzheimer's disease, characterized by the cerebral deposition of beta-amyloid plaques resulting from the abnormal processing of the transmembrane amyloid precursor protein (APP). The initiating event of cholesterol-induced atherosclerosis is the retention and accumulation of atherogenic apolipoprotein B (apoB) together with low-density lipoproteins in the vascular intima. Biglycan, a member of the small leucine-rich protein family, was suspected of contributing to this process. The individual and combined overexpressions of biglycan and apoB-100 were therefore examined on the cortical APP mRNA levels of transgenic mice by means of semiquantitative PCR. As compared with the control littermates, transgenic biglycan mice had significantly increased cortical APP695 (122%) and APP770 (157%) mRNA levels, while the double transgenic (apoB(+/-)xbiglycan(+/-)) mice did not exhibit any changes. These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias.

Kálmán J, Palotás M, Pákáski M, Hugyecz M, Janka Z, Palotás A. · University of Szeged, Department of Psychiatry, Hungary. · Eur J Anaesthesiol. · Pubmed #16884554 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Recent studies emphasize a positive correlation between (cardiac) surgical interventions and increased risk for developing Alzheimer's disease in the late postoperative period. Since amyloid precursor protein and its neurotoxic derivatives play key roles in the development of Alzheimer's dementia, the impact of several agents used in the intra- and perioperative period is examined. METHOD: Amyloid precursor protein concentrations were assessed by semi-quantitative Western-immunoblot in brains of rats following intraperitoneal treatment with diazepam and midazolam. RESULTS: There were no significant changes in the amyloid precursor protein concentrations. CONCLUSION: Both diazepam and midazolam are considered to be relatively safe with respect to amyloid precursor protein metabolism.

Zana M, Szécsényi A, Czibula A, Bjelik A, Juhász A, Rimanóczy A, Szabó K, Vetró A, Szucs P, Várkonyi A, Pákáski M, Boda K, Raskó I, Janka Z, Kálmán J. · Department of Psychiatry, Alzheimer's Disease Research Center, Faculty of Medicine, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, 6 Semmelweis St., Szeged, H-6725, Hungary. · Biochem Biophys Res Commun. · Pubmed #16696946 No free full text.

Abstract: The aim of the present study was to investigate the oxidative status of lymphocytes from children (n=7) and adults (n=18) with Down's syndrome (DS). The basal oxidative condition, the vulnerability to in vitro hydrogen peroxide exposure, and the repair capacity were measured by means of the damage-specific alkaline comet assay. Significantly and age-independently elevated numbers of single strand breaks and oxidized bases (pyrimidines and purines) were found in the nuclear DNA of the lymphocytes in the DS group in the basal condition. These results may support the role of an increased level of endogenous oxidative stress in DS and are similar to those previously demonstrated in Alzheimer's disease. In the in vitro oxidative stress-induced state, a markedly higher extent of DNA damage was observed in DS children as compared with age- and gender-matched healthy controls, suggesting that young trisomic lymphocytes are more sensitive to oxidative stress than normal ones. However, the repair ability itself was not found to be deteriorated in either DS children or DS adults.

Palotás M, Palotás A, Bjelik A, Pákáski M, Hugyecz M, Janka Z, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721, Szeged, Semmelweis u. 6, Hungary. · Neurochem Res. · Pubmed #16258851 No free full text.

Abstract: The incidence of Alzheimer's disease is elevated after exposure to surgical interventions. Since amyloid precursor protein (APP) and its neurotoxic derivatives play key roles in the development of Alzheimer dementia, the role of general anesthesia is controversial in the development of cognitive decline. As such, the effect of anesthetics on APP protein and mRNA levels was assessed utilizing semiquantitative Western-immunoblot and reverse transcription polymerase chain reaction (RT-PCR) in brains of rats following intraperitoneal treatment with propofol and thiopental. The anesthetics did not change cortical APP protein and mRNA concentration considerably. These results indicate that both propofol and thiopental are considered to be relatively safe with respect to APP metabolism.

Juhász A, Rimanóczy A, Boda K, Vincze G, Szlávik G, Zana M, Bjelik A, Pákáski M, Bódi N, Palotás A, Janka Z, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, Szeged, Hungary. · Neurochem Res. · Pubmed #16258842 No free full text.

Abstract: Multiple genetic and environmental factors regulate the susceptibility to Alzheimer's disease (AD). Recently, several independent studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain, called 24-hydroxylase (CYP46A1) is located, has been linked with AD. The single nucleotide polymorphism (T/C) in intron 2 of CYP46 gene has been found to confer the risk for AD. The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process. A case-control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD. The frequency of the CYP46 C allele was similar (chi2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561-1.274) in both groups (CNT: 27%; 95% CI: 21.3-33.4; AD 30%; 95% CI: 25.0-36.3). The ApoE varepsilon4 allele was significantly over-represented (chi2=11.029, df=2, P=0.004) in the AD population (23.2%; 95% CI: 18.2-29.0) when compared with the CNT (11.3%; 95% CI: 7.4-16.6). The presence or absence of one or two CYP46C alleles together with the ApoE varepsilon4 allele did not increase the risk of AD (OR=3.492; 95% CI: 1.401-8.707; P<0.007 and OR=3.714; 95% CI: 1.549-8.908; P<0.003, respectively). Our results indicate that the intron 2 T/C polymorphism of CYP46 gene (neither alone, nor together with the varepsilon4 allele) does not increase the susceptibility to late-onset sporadic AD in the Hungarian population.

Juhász A, Palotás A, Janka Z, Rimanóczy A, Palotás M, Bódi N, Boda K, Zana M, Vincze G, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, Semmelweis u 6, H-6721, Szeged, Hungary. · Neurochem Res. · Pubmed #16176061 No free full text.

Abstract: Apolipoprotein E gene (Apo(epsilon)) has three common alleles (epsilon2, epsilon3, and epsilon4), of which epsilon4 has been shown to be associated with an increased risk for Alzheimer's disease (AD). Possible additional genetic factors, like the -491A variant of ApoE promoter may modify the development of AD, independently of the ApoE allele status. The objective of this study was to investigate whether A/T allelic polymorphism at site-491 of the ApoE promoter is associated with AD in a Hungarian population. The genomic DNA isolated from peripheral blood lymphocytes of 52 late-onset AD and 53 control individuals was used as a template for the two examined polymorphisms and PCR assay was applied. The epsilon4 allele was significantly over-represented in the AD group (28%) as compared with the control population (7%). No significant differences have been found between the control and the AD populations regarding the occurrence of the promoter A allele frequencies (control: 77%, AD: 70%). However, the AA genotype was more frequent in the AD group (48%) than in the control (10%) when the presence of epsilon4 allele was also considered. It is unlikely therefore that the -491A variant of the ApoE promoter gene is an independent risk factor in the Hungarian AD population, but a linkage disequilibrium exists between the two examined mutations.

Zana M, Juhász A, Rimanóczy A, Bjelik A, Baltás E, Ocsovszki I, Boda K, Penke B, Dobozy A, Kemény L, Janka Z, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, 6 Semmelweis Street, Szeged H-6725, Hungary. · Neurobiol Aging. · Pubmed #15961188 No free full text.

Abstract: In the present pilot investigation, the susceptibility of T-lymphocytes from Alzheimer's disease (AD) subjects (n=22) and aged-matched, non-demented controls (CNT) (n=12) was examined with ultraviolet (UV) B light-induced apoptosis in vitro. The basal apoptotic ratios were similar in both groups. However, the AD lymphocytes displayed significantly (p<0.0001) lower apoptotic levels than those of the CNT lymphocytes at all of the applied UVB exposure doses (100, 200 and 300 mJ/cm(2)). These observations indicate that AD lymphocytes are more resistant than CNT lymphocytes to UVB irradiation.

Pákáski M, Bjelik A, Hugyecz M, Kása P, Janka Z, Kálmán J. · Alzheimer's Disease Research Centre, Department of Psychiatry, University of Szeged, Semmelweis 6, H-6725 Szeged, Hungary. · Neurochem Int. · Pubmed #15955598 No free full text.

Abstract: Comorbid depression of Alzheimer's disease (AD) is a common mood disorder in the elderly and a broad spectrum of antidepressants have been used for its treatment. Abeta peptides and other derivatives of the amyloid precursor protein (APP) have been implicated as central to the pathogenesis of AD. However, the functional relationship of APP and its proteolytic derivatives to antidepressant therapy is not known. In this study, Western blotting was used to test the ability of the tricyclic antidepressant (TCA) imipramine or the selective serotonin reuptake inhibitor (SSRI) citalopram to change the release of APP and the protein kinase C (PKC) content. Both antidepressants increased APP secretion in primary rat neuronal cultures. Imipramine or citalopram enhanced the level of secreted APP by 3.2- or 3.4-fold, respectively. Increases in PKC level were observed only after imipramine treatment. These in vitro data suggest that both TCA and SSRI are able to interfere with the APP metabolism. Imipramine promotes the non-amyloidogenic route of APP processing via stimulatory effects on PKC. We propose that PKC is not involved in the mechanism underlying the effects of citalopram on the APP metabolism. Since the secreted APP is not further available for the pathological cleavage of beta- and gamma-secretases, antidepressant medication might be beneficial in AD therapy.

Kálmán J, Kitajka K, Pákáski M, Zvara A, Juhász A, Vincze G, Janka Z, Puskás LG. · Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, Faculty of Medicine, University of Szeged, Semmelweis u. 6. H-6725 Szeged, Hungary. · Psychiatr Genet. · Pubmed #15722950 No free full text.

Abstract: Since the function and metabolism of peripheral lymphocytes is known to be altered in Alzheimer's disease (AD), a pilot study was carried out to examine differences in gene expression profiles of these cells in 16 AD patients and aged control probands. Using a cDNA microarray representing 3200 distinct human genes, we identified 20 candidate genes whose expression is altered in AD lymphocytes compared with the control probands. Among these were the alpha2C-adrenoreceptor gene, known to regulate blood pressure and learning, the defensin, histocompability complex enhancer-binding protein, carboxypeptidase M, and the Fc fragment of IgE known to be involved in cellular and humoral immune responses. Others, like human cell death protein, TRAIL, and galectin-4 participate in the regulation of apoptosis. Real-time quantitative reverse transcription-polymerase chain reaction analysis was performed in order to confirm the expression changes in AD lymphocytes, and it could detect down-regulation of defensin and alpha2c-adrenoceptor genes, while other genes seemed unaltered in their expression, including heat-shock protein (hsp90), cholesteryl ester transfer protein, and apolipoprotein B100 (apoB). The altered expression profile of these genes might be connected with the previously reported AD-specific lymphocyte abnormalities. It remains to be elucidated, however, how these genes are related to the pathomechanism of dementia and whether the gene expression differences of AD lymphocytes reflect disease traits or stage processes.

Boda K, Kálmán J, Janka Z. · Department of Medical Informatics, University of Szeged, Hungary. · Stud Health Technol Inform. · Pubmed #15460732 No free full text.

This publication has no abstract.

Palotás A, Puskás LG, Kitajka K, Palotás M, Molnár J, Pákáski M, Janka Z, Penke B, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary. · Eur J Pharmacol. · Pubmed #15336942 No free full text.

Abstract: Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. We have demonstrated that gene expression profiles of lymphocytes from patients with Alzheimer dementia differ from that seen with controls, with alpha(2)-adrenoceptor being the most highly repressed transcript. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer patients and control individuals to assess the impact of mirtazapine, the novel antidepressant with alpha(2)-adrenoceptor antagonistic activities, on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with mirtazapine were identified and categorized based on similarities in biological functions. This analysis revealed that selected biological processes, including protein metabolism, cytoskeleton integrity, immune response, cellular plasticity, and neurotransmission, are involved in early phases of administration of this antidepressant. In addition, although it was possible to identify common targets, the expression profiles of Alzheimer lymphocytes differed mainly in their magnitude from those seen with controls. These results confirm the usefulness of the gene array approach for studying Alzheimer-specific changes in the periphery and suggest that the expression of genes of Alzheimer lymphocytes is modulated differently by mirtazapine, which correlates with the pathology.

Palotás A, Puskás LG, Kitajka K, Palotás M, Molnár J, Pákáski M, Janka Z, Penke B, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Hungary. · Neurochem Res. · Pubmed #15260135 No free full text.

Abstract: Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. In certain neurodegenerative disorders, such as in Alzheimer's disease, lymphocytes have been used to assess mirror changes that thought to occur in the brain. Gene expression profiles of lymphocytes from Alzheimer patients have been shown to differ from that seen with controls. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer's disease patients and control individuals to assess the impact of the selective serotonine reuptake inhibitor citalopram on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with citalopram were identified and categorized based on similarities in biological functions. This analysis revealed that the overexpression of genes in control and Alzheimer white blood cells by citalopram are implicated in cell survival. Apart from this, citalopram did not markedly alter genes involved in other molecular functions in control cells. In contrast, alteration of genes implicated in ionic currents, cell-adhesion, immune mechanism, and adrenergic functions, were also observed in Alzheimer lymphocytes. The expression of genes of Alzheimer lymphocytes by citalopram is modulated differently which may correlate with the pathology.

Palotás A, Penke B, Palotás M, Kenderessy AS, Kemény L, Kis E, Vincze G, Janka Z, Kálmán J. · Department of Medical Chemistry, University of Szeged, Szeged, Hungary. · Skin Pharmacol Physiol. · Pubmed #15258451 No free full text.

Abstract: BACKGROUND: Antipsychotics are widely used in the treatment of behavioral and psychological symptoms of dementia. A low frequency of Alzheimer's disease in patients with schizophrenia is reported, and it has been proposed that antipsychotic medications, such as haloperidol, may be responsible. Disruption of intracellular calcium levels is considered to play a key role in beta-amyloid-induced neurotoxicity in Alzheimer's disease. Haloperidol has also been reported to interact with calcium homeostasis through dopamine-2 and sigma-1 receptors, and other, yet unknown mechanisms. OBJECTIVE: Therefore, we investigated whether differences in the basal intracellular free calcium levels of cultured cutaneous fibroblasts--cells that do not express dopamine-2 and sigma-1 receptors--derived from sporadic Alzheimer patients and from age-matched control individuals after haloperidol treatment might be present. METHODS: Intracellular calcium level was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. RESULTS: Alzheimer cells exhibited significantly lower calcium level as compared to the control cultures. Exposure of fibroblasts to beta-amyloid peptide resulted in increased calcium concentration of the control cells, but not of Alzheimer fibroblasts. Co-incubation of cultures with a therapeutic dose of haloperidol blocked the beta-amyloid-induced elevation of calcium. CONCLUSION: This finding indicates that haloperidol efficiently countervails ionic imbalance and suggests that it may serve as a potential agent in alleviating neurotoxic effects of beta-amyloid peptide.

Kálmán J, Juhász A, Janka Z, Rakonczay Z, Abrahám G, Boda K, Farkas T, Penke B. · No affiliation provided · Atherosclerosis. · Pubmed #15177135 No free full text.

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