Alzheimer Disease: Riederer P

Koutsilieri E, Riederer P. · Clinical Neurochemistry (National Parkinson Foundation Center of Excellence Research Laboratory), Department of Psychiatry and Psychotherapy, University of Wurzburg, Germany. · Parkinsonism Relat Disord. · Pubmed #18267259 No free full text.

Abstract: N-methyl-D-aspartate (NMDA) receptors play central roles in a number of physiological processes, including long-term potentiation in the hippocampus, synaptogenesis and synaptic plasticity. Excessive NMDA receptor activation has been implicated in the pathophysiology of chronic neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). With the discovery of the heterogeneity of NMDA receptors through molecular biological approaches, new targets have been identified for new-generation NMDA receptor antagonists. This short article focuses on the evidence for the involvement of NMDA receptor subtypes in neurodegenerative disorders and reviews the scarce advances in therapeutic approaches with "selective" NMDA subunit antagonists in PD and AD.

Hoyer S, Riederer P. · Department of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany. · Neurochem Res. · Pubmed #17063393 No free full text.

Abstract: Nosologically, Alzheimer disease (AD) is not a single disorder. A minority of around 400 families worldwide can be grouped as hereditary in origin, whereas the majority of all Alzheimer cases (approx. 25 million worldwide) are sporadic in origin. In the pathophysiology of the latter type, a number of susceptibility genes contribute to the disease among which are allelic abnormalities of the apolipoprotein E4 gene pointing to a link between disturbed cholesterol metabolism and sporadic AD. Cholesterol is a main component of membrane composition enriched in microdomains and is functionally linked to the proteolytic processing of amyloid precursor protein (APP). In sporadic AD, a marked diminution of both membrane phospholipids and cholesterol has been found. Evidence has been provided that high plasma cholesterol may protect from AD. In contrast to these well documented abnormalities observed in AD patients, it was assumed that an elevated cholesterol concentration might favour the generation of beta-amyloid and, thus, AD. However, a series of in vitro-and in vivo-studies did not provide evidence for the assumption that an enhanced cholesterol concentration increased betaA4-production. A harsh reduction of membrane cholesterol only caused a "beneficial" effect of APP metabolism. However, this experimentally induced condition may not be compatible to sporadic AD. The application of statins in sporadic AD did not yield results to assume that this therapeutic strategy may prevent or treat successfully sporadic AD.

Riederer P, Hoyer S. · Institute of Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Laboratory, Clinic for Psychiatry and Psychotherapy, Bayerische Julius-Maximilians-University of Würzburg, Würzburg, Germany. · J Neural Transm. · Pubmed #17053873 No free full text.

Abstract: The glutamatergic system is the most widespread neurotransmitter system in the mammalian brain. It is connected to the acetylcholinergic neurotransmitter system to form the glutamatergic/aspartatergic-acetylcholinergic circuit, which is the morphobiochemical basis of learning, memory and cognition assisted by the glutamatergic N-methyl-D-aspartate receptor, which mediates long-term potentiation as the fundamental molecular mechanisms of these mental capacities. Glutamate and acetylcholine as ligands of the two neurotransmitter systems are products of the neuronal glucose metabolism as holds true also for advanced glycation end products (AGEs), which are markers of damaged and/or aged proteins. During normal aging, both the neurotransmitters glutamate and acetylcholine undergo strong functional variations. Their synthesis was found to be reduced as a common feature. In contrast, basal release of acetylcholine and receptor number decrease, whereas basal release of glutamate and receptor number increase. AGEs increase during aging obviously preferentially in glutamatergic pyramidal neurons in cerebral cortical layers prone to neurodegeneration. In sporadic Alzheimer disease (SAD), glutamate concentration was shown to fall since it may serve as a substitute for lacking glucose in the beginning of the disease. In contrast, glutamate receptor density was found to be much less involved indicating an excessive activation of the glutamatergic neurotransmitter system particularly via the NMDA receptor, mediating endogenous excitotoxicity. The morphological hallmarks of SAD neuritic plaques and neurofibrillary tangles have been demonstrated to crosslink with AGEs causing an increased rate of free radical production. First data from animal studies and investigations on human beings may indicate that the NMDA receptor antagonist memantine may have beneficial effects on the course of SAD and its clinical symptoms.

Wiltfang J, Lewczuk P, Riederer P, Grünblatt E, Hock C, Scheltens P, Hampel H, Vanderstichele H, Iqbal K, Galasko D, Lannfelt L, Otto M, Esselmann H, Henkel AW, Kornhuber J, Blennow K. · Molecular Neurobiology Lab, Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. · World J Biol Psychiatry. · Pubmed #16156480 No free full text.

Abstract: Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Gsell W, Jungkunz G, Riederer P. · Psychiatric, Psychotherapeutic and Neurological State Hospital, Lohr am Main, Germany. · Curr Pharm Des. · Pubmed #14754387 No free full text.

Abstract: A review of neurochemical research on classical neurotransmitters, i.e. acetylcholine, serotonin, noradrenaline, dopamine, glutamate, and GABA in Alzheimer's disease is presented. Findings are linked to the information processing system of the human brain to establish a more functional neurochemistry. On this basis, different pharmacotherapeutic strategies are discussed. Our conclusion is that current symptomatic therapy of Alzheimer's disease is insufficient. Besides therapy with acetylcholinesterase inhibitors, comedication to act on imbalances between serotonin and noradrenaline on the one site, and dopamine, glutamate and GABA on the other site should should be considered.

Riederer P, Danielczyk W, Grünblatt E. · Neurochemical Laboratory, Clinic for Psychiatry and Psychotherapy, Bayerische Julius-Maximilians-Universität Würzburg, Füchsleinstr 15, 97080 Würzburg, Germany. · Neurotoxicology. · Pubmed #14697902 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Hoyer S, Riederer P. · Abteilung für Pathochemie und Allgemeine Neurochemie, Universität Heidelberg. · Fortschr Neurol Psychiatr. · Pubmed #12947539 No free full text.

Abstract: Even though the clinical effectiveness of the presently used pharmaceutical therapy of sporadic Alzheimer Disease seems to be proven sufficient, their effective mechanisms are much less known or are disregarded in the evaluation of the clinical effects. However, it seems to be inevitable to know both clinical effect and effective mechanisms of pharmaceutics in order to be able to judge their adversity and benefit. In reference to the pharmaceutics implemented on sporadic AD in Germany, total different effective mechanisms are shown. In consideration of the shown pathomechanisms which have been recognized for sporadic AD, therapeutic rationales on application of Ginkgo biloba extract (EGb 761) and Memantine are evident. The application of acetylcholinesterase inhibitors, often looked on as agent of choice, is to be considered critically because of the danger of the occurrence of myopathological dysfunction, resp. the Gulf War Syndrome. Sophisticated and hastily advertised therapy strategies with statins or vaccination against beta A4 should not be used because of a lack of sufficient evidence based on the pathophysiological pattern of damage as known in sporadic AD. Future development must take in account that with sporadic AD aging influences cannot or can hardly be influenced. Therapeutic goals should consist to improve the cellular energy status and the membrane functioning.

Dukic-Stefanovic S, Schinzel R, Riederer P, Münch G. · Physiological Chemistry I, Biocenter, University of Würzburg, Germany. · Biogerontology. · Pubmed #11708614 No free full text.

Abstract: In Alzheimer's disease, age-related cellular changes such as compromised energy production and increased radical formation are worsened by the presence of AGEs as additional, AD specific stress factors. Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. Extracellular AGEs, which accumulate in ageing tissue (but most prominently on long-lived protein deposits like the senile plaques) exert chronic oxidative stress on neurons. In addition, they activate glial cells to produce free radicals (superoxide and NO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors might also become interesting novel therapeutic drugs for treatment of AD.

Mössner R, Schmitt A, Syagailo Y, Gerlach M, Riederer P, Lesch KP. · Department of Psychiatry, University of Würzburg, Federal Republic of Germany. · J Neural Transm Suppl. · Pubmed #11205152 No free full text.

Abstract: The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.

Durany N, Münch G, Michel T, Riederer P. · Department of Psychiatry, University of Würzburg, Germany. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #10654103 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the beta-peptide. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Advanced glycation endproducts (AGEs), which are formed by a non-enzymatic reaction of glucose with long-lived protein deposits, are potentially toxic to the cell, are present in brain plaques in AD, and its extracellular accumulation in AD may be caused by an accelerated oxidation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce nearly 50-fold more radicals than non-glycated proteins, and indirect (cellular) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell death. The development of drugs for the treatment of AD remains at a very unsatisfying state. However, pharmacological approaches which break the vicious cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical production. AGE inhibitors might be able to stop formation of AGE-modified beta-amyloid deposits, antioxidants are likely to scavenge intracellular and extracellular superoxide radicals and hydrogen peroxide before these radicals damage cell constituents or activate microglia, and anti-inflammatory drugs attenuating microglial radical and cytokine production.

Yamamoto-Sasaki M, Ozawa H, Saito T, Rösler M, Riederer P. · Clinical Neurochemistry, Department of Psychiatry, University of Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany. · Brain Res. · Pubmed #10196463 No free full text.

Abstract: Cyclic AMP (cAMP) is disrupted in the brain in dementia of the Alzheimer type (DAT). We investigated whether the cAMP reduction is accompanied by an alteration in the cAMP response element binding protein (CREB) downstream in DAT and control hippocampi. Immunoreactivity of pCREB was significantly decreased in DAT, while total CREB level was unchanged. These findings indicate that impaired cAMP signaling may contribute to the pathophysiology of the disease.

Grünblatt E, Bartl J, Zehetmayer S, Ringel TM, Bauer P, Riederer P, Jacob CP. · Clinical Neurochemistry, National Parkinson Foundation Centre of Excellence Research Laboratories, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Würzburg, Würzburg, Germany. · J Alzheimers Dis. · Pubmed #19276557 No free full text.

Abstract: Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. At present, diagnosis of AD is rather late in the disease. Therefore, we attempted to find peripheral biomarkers for the early diagnosis of AD. We investigated the profiles of 33 genes, previously found by our group to have altered expression in postmortem brains of AD. The gene profiles were studied via quantitative-real-time-reverse-transcription-polymerase-chain-reaction, in whole blood samples (collected with the PAXgene blood RNA system) isolated from a population clinically diagnosed with AD and healthy controls (1-year period/ up to 4 samples). Five genes showed significant correlation to the dementia score, Mini-Mental State Examination (MMSE). Focusing on the two genes with the smallest p-value, H3-histone and cannabinoid-receptor-2, notable increases in these genes were found in peripheral blood mRNA in subjects with lower MMSE scores. Seasonal variations in gene expression were not significant due to sample size, but did seem to vary due to time of sample withdrawal. In conclusion, gene expression profiling might be a promising method to investigating a large population with the aim of developing an early diagnosis of AD.

Grünblatt E, Zehetmayer S, Bartl J, Löffler C, Wichart I, Rainer MK, Jungwirth S, Bauer P, Danielczyk W, Tragl KH, Riederer P, Fischer P. · Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria. · J Psychiatr Res. · Pubmed #18603262 No free full text.

Abstract: OBJECTIVES: In ageing population, both Alzheimer's disease (AD) and depression are common. Significant depressive symptoms are often co-morbid with cognitive impairment and dementia. In this study, we attempted to find various factors and markers for both AD and depression in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. METHODS: The VITA-Study consisted of 305 healthy subjects, 174 subjects with depression only, 55 subjects diagnosed with AD only and 72 subjects with depression as well as AD. Associations between AD and/or depression to gene polymorphisms APO E (epsilon4), choline acetyltransferase (ChAT) 4G to A, serotonin-transporter gene promoter-length, dopamine-D4-receptor, ciliary-neurotrophic-factor-null mutation and brain-derived neurotrophic factor (C270T) and to various known factors were analyzed. RESULTS: AD and depression were significant associated. Significant risk factors found for AD were low education, low folic acid and depressive-symptoms, while for depression were low education and higher nonsteroidal anti-inflammatory drugs (NSAID) consume. Moreover, the ChAT polymorphism associated significant to depression. Gender, education, and ChAT significantly associated with the combination AD and/or depression. CONCLUSION: Such studies must be conducted cautiously, as co-morbidities and gene-environmental-social influences may sway the results dramatically. We found in the VITA-study significant association between depression and AD and between ChAT polymorphism and depression.

Grünblatt E, Zander N, Bartl J, Jie L, Monoranu CM, Arzberger T, Ravid R, Roggendorf W, Gerlach M, Riederer P. · Neurochemistry Laboratory, National Parkinson Foundation Centre of Excellence Laboratories, Clinic and Policlinic for Psychiatry and Psychotherapy, University of Würzburg, Germany. · J Alzheimers Dis. · Pubmed #18198416 No free full text.

Abstract: Sporadic Alzheimer's (AD) and Parkinson's disease (PD) are late-onset neurodegenerative diseases with tremendous impact on lives of affected individuals. There is a great probability of developing concurrent Parkinsonism in AD and vice-versa than would be predicted by independent prevalence of each disease. We hypothesize that in sporadic AD as well as PD a combination of environmental effects and gene expression may affect specific brain areas leading to neurodegeneration. We profiled gene expression of AD compared to PD and age matched controls post-mortem in the hippocampus, the gyrus-frontalis-medius (Gfm) and the cerebellum using Gene-Chip microarray (Affymetrix) and quantitative-real-time-RT-PCR. Twelve genes altered in similar manner in AD and PD, while four genes showed differential expression profiles between AD and PD in different brain regions (cannabinoid-receptor-2, Histone-cluster-1-H3e, nicotinic-cholinergic-receptor-alpha6 and beta-site-APP-cleaving enzyme-1). Knowledge of selective gene expression profile can lead to better understanding of disease pathology and development of specific diagnosis and effective therapy.

Tahirovic I, Sofic E, Sapcanin A, Gavrankapetanovic I, Bach-Rojecky L, Salkovic-Petrisic M, Lackovic Z, Hoyer S, Riederer P. · Department of Chemistry, Faculty of Science, University of Sarajevo, Sarajevo, Bosnia and Herzegovina. · J Neural Transm Suppl. · Pubmed #17982899 No free full text.

Abstract: It is believed that oxidative stress plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer's disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity against peroxyl (ORAC(-ROO)*) and hydroxyl (ORAC(-OH)*) free radical was measured in three different brain regions (hippocampus, cerebellum, and brain stem) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased antioxidant capacity has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy. Also, these abnormalities were not prevented by the icv pretreatment of glucose transport inhibitor 5-thio-D-glucose in the STZ-icv treated rats, suggesting different mechanism for STZ-induced central effects from those at the periphery. Similarities in the oxidative stress alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for new drugs in the treatment of sAD that have antioxidant activity.

Fischer P, Krampla W, Mostafaie N, Zehetmayer S, Rainer M, Jungwirth S, Huber K, Bauer K, Hruby W, Riederer P, Tragl KH. · Department of Psychiatry and Psychotheraphy, Medical University Vienna, Vienna, Austria. · J Neural Transm Suppl. · Pubmed #17982893 No free full text.

Abstract: The etiology of white matter hyperintensities (WMH) seen on T2-weighted cranial magnetic resonance images is a matter of debate. We investigated deep and periventricular WMH in the brains of a community-based cohort of 532 subjects aged 75-76 years. The objective of this study was to determine whether WMH at age of 75 years were associated rather with vascular factors than with degenerative factors. Arterial hypertension treated with antihypertensive drugs favored WMH, and WMH were found more frequently in subjects with focal vascular lesions. Additionally, we found significant associations between both, deep white matter and periventricular hyperintensities, and focal atrophy of medial temporal lobe structures. The odds ratio for deep WMH in subjects with more severe medial temporal atrophy was 4.4 (95%-CI: 1.9-9.8) that for periventricular hyperintensities was 3.9 (95%-CI: 1.7-8.8). These findings might indicate that not only vascular factors alone but also degenerative factors favor the occurrence of WMH after the age of 75 years.

Tahirovic I, Sofic E, Sapcanin A, Gavrankapetanovic I, Bach-Rojecky L, Salkovic-Petrisic M, Lackovic Z, Hoyer S, Riederer P. · Department of Chemistry, Faculty of Science, University of Sarajevo, Zmaja od Bosne 35, 71 000, Sarajevo, Bosnia and Herzegovina · Neurochem Res. · Pubmed #17605105 No free full text.

Abstract: It is believed that oxidative stress (OS) plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer's disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity (AC) against peroxyl (ORAC(-ROO) (*)) and hydroxyl (ORAC(-OH) (*)) free radicals (FR) was measured in three different brain regions: the hippocampus (HPC), the cerebellum (CB), and the brain stem (BS) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased AC has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy (PDN). Also, these abnormalities were not prevented by the intracerebroventricularly (icv) pretreatment of glucose transport inhibitor 5-thio-D: -glucose (TG) in the STZ-icv treated rats, suggesting different mechanism of STZ-induced central effects from those at the periphery. Similarities of the OS alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for the new drugs in the treatment of sAD that have antioxidant activity. In the STZ-induced diabetic animals the existence of PDN was tested by the paw pressure test, 3 weeks following the diabetes induction. Mechanical nociceptive thresholds were measured three times at 10-min intervals by applying increased pressure to the hind paw until the paw-withdrawal or overt struggling was elicited. Only those diabetic animals which demonstrated decreased withdrawal threshold values in comparison with the control non-diabetic animals (C) were considered to have developed the PDN.

Sofic E, Sapcanin A, Tahirovic I, Gavrankapetanovic I, Jellinger K, Reynolds GP, Tatschner T, Riederer P. · Department of Chemistry, Faculty of Science, University of Sarajevo, Bosnia & Herzegovina. · J Neural Transm Suppl. · Pubmed #17447414 No free full text.

Abstract: Oxidative stress has been associated with damage and progressive cell death that occurs in neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). The aim of this study was to investigate the antioxidant capacity in postmortem motor cortex (MC), nucleus caudatus (NC), gyrus temporalis (GT) and substantia nigra (SN) from controls (C) and patients with PD and AD. The initial samples consisted of 68 subjects of PD, AD and C. Brains were matched for age, sex and postmortem time. Brain tissue was homogenized in a phosphate buffer pH 7.3 and separated with two-step centrifugation at 15,000rpm for 30 min and 15,000 rpm for 10 min at 4 degrees C. Antioxidant capacity in the supernatants was measured using the oxygen radical absorbance assay (ORAC). The results showed that in the SN of parkinsonian's brain the balance between production of free radicals and the neutralization by a complex antioxidant system is disturbed. No changes in the antioxidant capacity of postmortem MC and NC of parkinsonian's brain in comparison with C were found. In the SN of parkinsonian's brain, antioxidant capacity seems to be lower in comparison with C (p < 0.05). Antioxidant capacity against peroxyl radical showed that MC of AD patients was lower than in the MC of C (p < 0.005). In NC of AD patients the antioxidant capacity against hydroxyl radical was increased in comparison with C (p < 0.04). No changes in the antioxidant capacity were found in brain tissues of AD in comparison with C, when CuSO4 was used as a free radical generator.

Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grünblatt E. · Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Research Laboratories, Clinic and Policlinic for Psychiatry and Psychotherapy, University of Würzburg, Germany. · J Alzheimers Dis. · Pubmed #17361039 No free full text.

Abstract: Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD.

Grünblatt E, Koutsilieri E, Hoyer S, Riederer P. · Institute of Clinical Neurochemistry, National Parkinson Foundation Centre of Excellence Laboratories, Bayerische Julius-Maximilians- University of Würzburg, D-97080 Würzburg, Germany. · J Alzheimers Dis. · Pubmed #16914836 No free full text.

Abstract: Streptozotocin is well known inducer of experimental diabetes mellitus when injected peripherally. However, when administered intracerebroventricular, streptozotocin showed a whole spectrum of specific biochemical and behavioural alterations with regard to cognitive functions, feeding, nociception, brain glucose metabolism, neurotransmission and oxidative stress, without producing arterial hyperglycaemia, similarly to Alzheimer's disease. In order to reveal the mechanism of action of neurodegeneration in streptozotocin rat model we investigated the expression of several genes involved in inflammation, oxidative stress, growth- and transcription-factors in the cortex, striatum and cerebellum, using real-time quantitative RT-PCR. Genes such as GDNF, BDNF and integrin-alpha-M were up-regulated, while immediate-early-gene-transcription-factor NGF-IB and metallothionein-1/2 were down-regulated in the cortex of streptozotocin-treated rats. Conversely, NGF-IB, GDNF and BDNF mRNA expression did not alter in the striatum and cerebellum. However, integrin alpha-M and metallothionein-1/2 expressions decreased significantly in the striatum and increased in the cerebellum. These gene changes may provide an insight into the cascade of physiological abnormalities following the inhibition of neuronal insulin signal transduction. Additionally, similarities to neuronal cell death in sporadic Alzheimer's disease may become apparent.

Grünblatt E, Hupp E, Bambula M, Zehetmayer S, Jungwirth S, Tragl KH, Fischer P, Riederer P. · Ludwig Boltzmann Society, L. Boltzmann Institute of Aging Research, Vienna, Austria. · J Affect Disord. · Pubmed #16797081 No free full text.

Abstract: BACKGROUND: Neurotrophic factors are known to play an important role in the survival and differentiation of many types of neurons during development. Both brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) may act cooperatively in modulating the development and functioning of synapses. Both these neurotrophic factors were intensely investigated with regard to depression without conclusive results. METHODS: We have investigated the possible use of both CNTF null-mutation and BDNF polymorphism C270T as biomarkers for depression in the Vienna Transdanube Aging (VITA) study. The VITA is a prospective community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. RESULTS: We found no association between CNTF null-mutation and BDNF C270T polymorphism to any depressive symptoms after exclusion of demented subjects. CONCLUSION: These results call in question the hypothesis that either BDNF or CNTF can be used as molecular markers for depression or late onset depression in the elderly.

Völkel W, Sicilia T, Pähler A, Gsell W, Tatschner T, Jellinger K, Leblhuber F, Riederer P, Lutz WK, Götz ME. · Department of Toxicology, University of Würzburg, Würzburg, Germany. · Neurochem Int. · Pubmed #16483694 No free full text.

Abstract: In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.

Salkovic-Petrisic M, Tribl F, Schmidt M, Hoyer S, Riederer P. · Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia. · J Neurochem. · Pubmed #16412093 No free full text.

Abstract: The insulin-resistant brain state is related to late-onset sporadic Alzheimer's disease, and alterations in the insulin receptor (IR) and its downstream phosphatidylinositol-3 kinase signalling pathway have been found in human brain. These findings have not been confirmed in an experimental model related to sporadic Alzheimer's disease, for example rats showing a neuronal IR deficit subsequent to intracerebroventricular (i.c.v.) treatment with streptozotocin (STZ). In this study, western blot analysis performed 1 month after i.c.v. injection of STZ showed an increase of 63% in the level of phosphorylated glycogen synthase kinase-3alpha/beta (pGSK-3alpha/beta) protein in the rat hippocampus, whereas the levels of the unphosphorylated form (GSK-3alpha/beta) and protein kinase B (Akt/PKB) remained unchanged. Three months after STZ treatment, pGSK-3alpha/beta and Akt/PKB levels tended to decrease (by 8 and 9% respectively). The changes were region specific, as a different pattern was found in frontal cortex. Structural alterations were also found, characterized by beta-amyloid peptide-like aggregates in brain capillaries of rats treated with STZ. Similar neurochemical changes and cognitive deficits were recorded in rats treated with i.c.v. 5-thio-d-glucose, a blocker of glucose transporter (GLUT)2, a transporter that is probably involved in brain glucose sensing. The IR signalling cascade alteration and its consequences in rats treated with STZ are similar to those found in humans with sporadic Alzheimer's disease, and our results suggest a role for GLUT2 in Alzheimer's pathophysiology.

Glatz DC, Rujescu D, Tang Y, Berendt FJ, Hartmann AM, Faltraco F, Rosenberg C, Hulette C, Jellinger K, Hampel H, Riederer P, Möller HJ, Andreadis A, Henkel K, Stamm S. · Molecular and Clinical Neurobiology, Department of Psychiatry Ludwig-Maximilians-University, Munich, Germany. · J Neurochem. · Pubmed #16371011 No free full text.

Abstract: Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in tauopathies, which include Alzheimer's disease (AD). Tau is a microtubule-associated protein whose transcript undergoes alternative splicing in the brain. Exon 10 encodes one of four microtubule-binding repeats. Exon 10 inclusion gives rise to tau protein isoforms containing four microtubule-binding repeats (4R) whereas exclusion leads to isoforms containing only three repeats (3R). The ratio between 3R and 4R isoforms is tightly controlled via alternative splicing in the human adult nervous system and distortion of this balance results in neurodegeneration. Previous studies showed that several splicing regulators, among them hTRA2-beta1 and CLK2, regulate exon 10 alternative splicing. Like most splicing factors, htra2-beta and clk2 pre-mRNAs are regulated by alternative splicing. Here, we investigated whether human postmortem brain tissue of AD patients reveal differences in alternative splicing patterns of the tau, htra2-beta, presenilin 2 and clk2 genes when compared with age-matched controls. We found that the splicing patterns of all four genes are altered in affected brain areas of sporadic AD patients. In these affected areas, the amount of mRNAs of tau isoforms including exon 10, the htra2-beta1 isoform and an inactive form of clk2 are significantly increased. These findings suggest that a misregulation of alternative splicing seems to contribute to sporadic AD.

Grünblatt E, Schlösser R, Fischer P, Fischer MO, Li J, Koutsilieri E, Wichart I, Sterba N, Rujescu D, Möller HJ, Adamcyk W, Dittrich B, Müller F, Oberegger K, Gatterer G, Jellinger KJ, Mostafaie N, Jungwirth S, Huber K, Tragl KH, Danielczyk W, Riederer P. · Clinic for Psychiatry and Psychotherapy, Department Clinical Neurochemistry, Bayerische Julius-Maximilians-University, Fuchsleinstr 15, Würzburg, Germany. · Neurobiol Aging. · Pubmed #15653171 No free full text.

Abstract: Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.