Michael Rösler

Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type.

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.

Free radicals in Alzheimer’s disease

Alzheimers disease is a neurodegenerative disorder comprising multisystem atrophies probably caused by multifactorial processes. The disease is characterized by typical neuropathology, impaired synaptic function and massive cell loss. The pathobiochemistry of this disorder involves oxidative stress, which accumulates free radicals leading to excessive lipid peroxidation and neuronal degeneration in certain brain regions. Moreover, radical induced disturbances of DNA, proteins and lipid membranes have been measured. The hypothesis has been proposed that cellular events involving oxidative stress may be one basic pathway leading to neurodegeneration in Alzheimers disease. In this work we report evidence for increased oxidative stress and disturbed defense mechanisms in Alzheimers disease, which may result in a self-propagating cascade of neurodegenerative events. Furthermore it is evident from experimental data, that aggregation of beta-amyloid and beta-amyloid toxicity is favourably caused by oxidative stress. Therefore, oxidative stress plays a key role in the conversion of soluble to unsoluble beta-amyloid, suggesting that oxidative stress is primary to the beta-amyloid cascade.

Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology.

Summary. Several lines of evidence indicate that dopaminergic neurotransmission is involved in the regulation of impulsive aggression and violence and that genetically determined variability in dopaminergic gene expression modifies complex traits including that of impulsivity and aggression. In this study we report an association of the dopamine D3 receptor (DRD3) polymorphism with impulsiveness according to Eysencks EIQ and scores on the German short version of the Wender Utah Rating Scale (WURS-k), which we used for the assessment of a history of ADHD-related symptoms. This association was detected in a group of violent offenders, but not in non-violent individuals. Highest scores of EIQ impulsiveness and of the WURS-k were found in heterozygous violent individuals, while homozygotes showed significant lower rating scores, suggesting an heterosis effect. The results of our study suggest that variations of the DRD3 gene are likely involved in the regulation of impulsivity and some psychopathological aspects of ADHD related to violent behavior.

Free radicals in Alzheimer’s dementia: currently available therapeutic strategies

Substantial evidence now exists that oxidative stress may play an important role in the etiopathogenesis of DAT. The different sources of oxidative stress in DAT are suggesting several pharmacological opportunities for influencing the disease. It is possible to distinguish 2 major types of possible therapeutic agents according to their pharmacological point of attack. 1. Radical scavengers, agents directly interacting with free radicals. Candidates of this type are gingko biloba, vitamins A, C, E and estrogen. 2. Antioxidants, which are able to prevent or decrease the production of free radicals by use of specific neuropharmacological properties. Candidates are selegiline, a MAO-B inhibitor well established in the therapy of Parkinsons disease, and tenilsetam, which is believed to be an AGE-inhibitor. Recent in vitro studies have demonstrated the efficacy of both types of therapeutic agents by preventing or delaying oxidative neural damage. Some clinical data exist regarding the antidementive properties particularly in terms of gingko biloba, selegiline and vitamin E. The efficacy studies about these compounds seem to indicate a promising future strategy in the therapy of DAT. But it is too early to draw definite conclusions since it is well known that all of our candidate substances do not act specifically as radical scavengers or antioxidants.

Potential genetic markers of sporadic Alzheimer's dementia.

Polymorphisms within the genes encoding apolipoprotein E (ApoE), apolipoprotein CI (ApoCI), α1-antichymotrypsin (ACT), the low-density lipoprotein (LDL) receptor and lipoprotein lipase were investigated in patients suffering from Alzheimers dementia and non-demented psychiatric patients as control subjects. The ApoE allele 4, well known as a risk factor in Alzheimers disease, and the ApoCI allele A2, which is closely linked to the ApoE allele 4, were found elevated in the index group. Concerning the polymorphism within exon 8 of the LDL receptor (alanin/threonin), there was also a predominance of the allele carrying threonin in the index group, which barely missed significance. Distribution of the polymorphisms of ACT and lipoprotein lipase were similar in both groups investigated. We conclude that, apart from the ApoE allele 4, other genetically regulated factors like ApoCI and the LDL receptor modulate the individual risk for Alzheimers disease.

Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer's disease.

Previous studies reported disruption of adenylyl cyclase (AC)-cyclic AMP (cAMP) signal transduction in brain of Alzheimers disease (AD). We also demonstrated that basal and stimulated AC activities in the presence of calcium and calmodulin (Ca(2+)/CaM) were significantly decreased in AD parietal cortex. In the present study, we examined the amounts of Ca(2+)/CaM-sensitive types I and VIII AC, and Ca(2+)/CaM-insensitive type VII AC in the postmortem hippocampi from AD patients and age-matched controls using immunoblotting. The specificities of the anti-type VII and VIII AC antibodies were confirmed by preabsorption with their specific blocking peptides. We observed a significant decrease in the level of type I AC and a tendency to decrease in the level of type VIII AC in AD hippocampus. On the other hand, the level of type VII AC showed no alteration between AD and controls. A body of evidence from the studies with invertebrates and vertebrates suggests that types I and VIII AC may play an essential role in learning and memory. Our finding thus firstly demonstrated that a specific disruption of the Ca(2+)/CaM-sensitive AC isoforms is likely involved in the pathophysiology in AD hippocampus.

ADVANCED GLYCATION ENDPRODUCTS-ASSOCIATED PARAMETERS IN THE PERIPHERAL BLOOD OF PATIENTS WITH ALZHEIMER'S DISEASE

Advanced glycation endproducts (AGEs), structural components of beta-amyloid plaques and neurofibrillary tangels, have been implicated in the pathogenesis of Alzheimers disease. AGE levels, measured by fluorescence, and their precursor molecules such as glucose and its Amadori product, fructosylamine, were measured to examine the question whether the reported increased level of AGEs in the brain is reflected in an increase in AGE-associated parameters in peripheral blood. Lactoferrin, proposed to play an important role in the interaction of AGEs with their receptors, was determined by ELISA. All AGE-associated parameters showed trends to lower values in patients with Alzheimers disease compared with non-demented controls. Albumin and total iron were not significantly different between the groups. In contrast to diabetes and renal failure, where high levels of AGEs and their precursors are present in tissue as well as in peripheral blood, elevated CNS AGE levels in patients with Alzheimers disease are manifested without detectable peripheral changes.

Alpha-1-antichymotrypsin bi-allele polymorphism, apolipoprotein-E tri-allele polymorphism and genetic risk of Alzheimer's syndrome

SummaryThe α1-antichymotrypsin and apolipoprotein-E polymorphisms were investigated in patients suffering from alzheimers syndrome and nondemented psychiatric inpatients as controls. The apolipoprotein E allele 4, well known as risk factor, tended to be elevated in the index group. The frequency of the α1-antichymotrypsin allele A was significantly increased in patients with Alzheimers syndrome: 0.647 vs. 0483 (chi-square test, p<0.05). We conclude that, apart from the apolipoprotein E allele 4, the α1-antichymotrypsin allele A possibly represents a second genetic factor increasing individuals risk for Alzheimers syndrome.

[Gender differences in self-descriptions of child psychopathology in attention deficit hyperactivity disorder].

Diagnosing attention deficit hyperactivity disorder (ADHD) in adults requires retrospective assessment of ADHD symptoms in childhood. The Wender Utah Rating Scale (WURS) and its German validated version (WURS-k) may offer a helpful tool to acertain relevant childhood problems associated with ADHD. Up to now validating data of the WURS-k were limited to male population. In a population of 69 female adult ADHD patients and 97 controls, ROC analysis indicated a sensitivity of 93% and specificity of 92% at a cut-off of 30 points in the WURS-k. This cut-off value is equivalent to those of males. Symptom report varies significantly by gender and females describe more internalizing problems while males report more externalizing behaviour. Regarding different subtypes according to DSM-IV males and females did not differ in the items of the WURS-k.

Association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and increased of psychiatric diseases

We report a possible association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and psychiatric diseases. Prior findings that the mutant allele frequency is not significantly elevated in patients suffering from neurological diseases are confirmed. The frequency of the mutant allele was higher among psychiatric patients (0.192, n = 297) than among healthy controls and neurological patients (0.142, n = 267). This difference (one-tailed 2 x 2 chi-square test, P < 0.05) might be evidence that disturbances in the neurotrophic factor system could play a crucial role in the etiopathogenesis of psychiatric disorders, mainly psychoses.