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T Arendt

Publications and source records attributed to T Arendt.

At least 19 recordsLinked to original sources
PubMed2006

The significance of the cholinergic system in the brain during aging and in Alzheimer's disease.

Acetylcholine is widely distributed in the nervous system and has been implicated to play a critical role in cerebral cortical development, cortical activity, controlling cerebral blood flow and sleep-wake cycle as well as in modulating cognitive performances and learning and memory processes. Cholinergic neurons of the basal forebrain complex have been described to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. Basal forebrain cholinergic cell loss is also a consistent feature of Alzheimer's disease, which has been suggested to cause, at least partly, the cognitive deficits observed, and has led to the formulation of the cholinergic hypotheses of geriatric memory dysfunction. Impaired cortical cholinergic neurotransmission may also contribute to beta-amyloid plaque pathology and increase phosphorylation of tau protein the main component of neurofibrillar tangles in Alzheimer's disease. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic dysfunction, beta-amyloid formation and deposition, and tau pathology in Alzheimer's disease, would allow to derive potential treatment strategies to pharmacologically intervene in the disease-causing signaling cascade.

Acetylcholine↗
PubMed2005

Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions.

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons. In this study NGF-protein levels were determined in areas of the basal forebrain cholinergic system, its projection areas as well as the striatum and the cerebellum after long-term exposure (6 and 9 months) to ethanol and a phase of withdrawal in male Sprague-Dawley rats. 6-month alcohol treatment led to an increase of NGF to 650-850% of controls in the basal forebrain and the septum and to a 210-485% increase in the cholinergic projection areas (anterior cortex, hippocampus and olfactory bulb). After 9 months exposure to ethanol, a decrease of NGF by 16% in the frontal cortex was observed compared to controls. In the other brain regions no differences in NGF expression were detectable at this time-point. These results support the idea of an endogenous neuroprotective mechanism acting through a transient NGF induction followed by a decrease in NGF-levels during the course of further neuronal degeneration.

Acetylcholine↗
PubMed2005

Phosphorylation of the tau protein sequence 199-205 in the hippocampal CA3 region of Syrian hamsters in adulthood and during aging.

Paired helical filaments formed by the abnormally phosphorylated microtubule-associated tau are a main sign of Alzheimer's disease and other neurodegenerative disorders. The hippocampal CA3 region, a brain region with a high degree of synaptic plasticity, is known to be strongly involved in tau hyperphosphorylation in several neurodegenerative diseases. In addition, reversible tau phosphorylation was observed during hibernation in European ground squirrels. The present study provides data on the tau phosphorylation status in the hippocampus of euthermic Syrian hamsters (Mesocricetus auratus), laboratory animals potentially prone to hibernation. Mossy fibers in the CA3 region of all investigated hamsters were immunostained using an antiserum detecting phospho-serine 199 of tau. A similar staining pattern was obtained with CP-13 detecting phospho-serine 202. In contrast, the monoclonal antibody AT8, recognizing both phosphorylated serine 202 and threonine 205, stained the CA3 region only in old hamsters. These findings implicate an additional link between aging, tau phosphorylation and synaptic plasticity. Furthermore, the presented data allow analyses whether tau phosphorylation is reversible in these facultative hibernators and versatile laboratory animal as it was recently shown for the hibernation cycle of European ground squirrels.

Age Factors↗
PubMed2005

Association between global brain volume and the rate of cognitive change in elderly humans without dementia.

Patients with mild cognitive deficits experience different types of evolution. They are at increased risk of developing dementia, but they have also a chance of remaining stable in cognition or of improving. We investigated whether global brain volume, callosal size and hippocampal size are associated with the rate of cognitive change in elderly without dementia. Volumetric MR images were recorded from 39 controls and 35 patients with questionable dementia who were followed up longitudinally for a mean of 2.3 years. The outcome measure was the annual change in the test score in the Structured Interview for the Diagnosis of Alzheimer's Dementia and Multi-Infarct Dementia, which includes all items of the Mini-Mental State Examination. Global brain volume, grey matter volume and white matter volume were the only significant independent predictors of the rate of cognitive change.

Aged↗
PubMed2004

Pseudophosphorylation of tau protein alters its ability for self-aggregation.

Filamentous tau protein deposits are a pathological hallmark of a group of neurodegenerative disorders (tauopathies). Tau protein in these aggregates is highly phosphorylated at different phosphorylation sites. Although tau filaments can be formed by heparin-induced aggregation of unphosphorylated recombinant tau, it is not known how tau phosphorylation modulates aggregation behaviour. Analysis of the effect of tau phosphorylation at defined single or multiple sites is hampered by the low specificity of protein kinases and the highly dynamic turnover of phosphorylation in vivo. To overcome this problem we employed site-directed mutagenesis to convert serine and threonine to aspartic acid or glutamic acid, which introduce a negative charge and conformational change that mimic phosphorylation. We tested 14 different mutated tau proteins for their propensity for self-aggregation and formation of tau filaments. Tau aggregation was monitored with thioflavin S fluorescence in the presence of different inducers such as heparin, Al3+, Fe2+ and Fe3+. We found that mutations in the N-terminal portion up to amino acid 208 mainly suppress tau aggregation, whereas mutations in the C-terminal region mainly lead to an enhanced aggregation. Mutations in the middle portion of tau showed a mixed picture of suppression and enhancement of aggregation. A single amino acid change Ser422Glu has aggregation-favouring properties with all four inducers.

Amino Acid Substitution↗
PubMed2003

Effect of advanced glycation endproducts on cell cycle and their relevance for Alzheimer's disease.

In Alzheimer's disease, neurons in affected regions re-enter the cell cycle, leave the G0 state and appear to be arrested at both the G1/S and G2/M phase with resulting cell death, predominantly by apoptosis. Further hallmarks of AD are crosslinked protein deposits (amyloid plaques and neurofibrillary tangles), which time-dependently become modified by "advanced glycation endproducts (AGEs)". Since AGEs activate both mitogenic and redox-sensitive pathways, they might be involved both in cell cycle re-entry and arrest.

Alzheimer Disease↗
PubMed2003

Anti-AGEing defences against Alzheimer's disease.

Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer's disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Abeta (beta-amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Abeta) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with beta-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-gamma. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound ("carbonyl stress") and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the "anti-glycation" treatment of AD.

Alzheimer Disease↗
PubMed2002

[Choledochal cysts in adult patients--presentation and clinical course].

HISTORY: A 35-year-old male was admitted with recurrent acute pancreatitis of unknown origin. He was found to have a cystic lesion in the upper abdomen believed to be a pancreatic pseudocyst (patient 1). A 59-year-old female with a choledochal cyst developed acute pancreatitis (patient 2). A 32-year-old male who had been operated upon for a choledochal cyst during childhood was admitted for upper abdominal pain, fever and vomitus (patient 3). INVESTIGATIONS AND DIAGNOSIS: Patient 1 was found to have a choledochal cyst type IV a according to TODANI. Patient 2 was diagnosed to have a choledochal cyst type Ib according to TODANI. The cyst was believed to contain a bile duct carcinoma. In patient 3, sonography showed an advanced Klatskin tumour with infiltration of the portal vein, the hepatic artery and the liver. Bile cytology confirmed the carcinoma. In all patients cholestasis was found. Pancreatic enzymes were elevated in patients 2 and 3. TREATMENT AND COURSE: Patient 1 underwent left hemihepatectomy and received a biliodigestive anastomosis. In patient 2 the choledochal cyst was resected while undergoing pylorus-preserving resection of the pancreatic head. The tumour suspected was confirmed and R0 resected. Patient 3 presented with an incurable bile duct carcinoma. He died 3 months later from multiple lung emboli. CONCLUSION: Choledochal cysts are associated with a 20 fold increase in the incidence of bile duct carcinoma.

Acute Disease↗
PubMed2002

Dysregulation of neuronal differentiation and cell cycle control in Alzheimer's disease.

Degeneration in Alzheimer's disease primarily occurs in those neurons that in the adult brain retain, a high degree of structural plasticity and, is associated with the activation of mitogenic signaling and cell cycle activation. Brain areas affected by neurofibrillary degeneration in Alzheimer's disease are structures involved in the regulation of "higher brain functions" that become increasingly predominant as the evolutionary process of encephalization progresses. The functions these areas subserve require a life-long adaptive reorganization of neuronal connectivity. With the increasing need during evolution to organize brain structures of increasing complexity, these processes of dynamic stabilization and de-stabilization become more and more important but might also provide the basis for an increasing rate of failure. The hypothesis is put forward that it is the labile state of differentiation of a subset of neurons in the adult brain that allows for ongoing morphoregulatory processes after development is completed but at the same time renders these neurons particularly vulnerable. Interferring with neuronal differentiation control might, thus, be a potential strategy to prevent neurodegeneration in Alzheimer's disease and related disorders.

Aged↗
PubMed2002

[Vascular dementia].

The term vascular dementia refers to dementia syndromes which are caused by hypoxic-ischaemic brain lesions. Lesions found in vascular dementia such as complete and incomplete infarctions, selective necroses, and others are nonspecific. The characteristics and severity of the clinical syndrome are determined by the size and topography of the ischaemic lesions. Among others, age and pre-existing brain atrophy are risk factors for the development of dementia based on vascular lesions. There is a high comorbidity of Alzheimer's disease and vascular dementia. It can be presumed that ischaemic lesions and Alzheimer-like pathological changes exert additive effects in the manifestation of the clinical dementia syndrome. The diagnostic process follows three steps: 1. presence of a dementia syndrome, 2. presence of cerebrovascular disease, 3. evidence for a relationship between 1 and 2. Present diagnostic criteria, such as "International Classification of Diseases" (ICD-10), "National Institute of Neurological Disorders," "Stroke-Associated Internationale pour la Reserche et l'Enseignement en Neurosciences" (NINDS-AIREN), and "Alzheimer's Disease Diagnostic and Treatment Centers" (ADDTC) describe differing constellations and show little congruence. Estimates of the prevalence depend highly on the set of criteria used. Hence, they differ considerably.

Aged↗
PubMed2002

Limited value of elevated erythrocyte sedimentation rate as an indicator of malignancy.

BACKGROUND: Patients with an elevated erythrocyte sedimentation rate (ESR) are often suspected of having malignant disease and are subjected to extensive investigations. Thus, the finding of an elevated ESR can result in considerable costs and might even be dangerous for the patient if invasive studies are ordered. OBJECTIVES: Our aims were to establish (i) the prevalence of malignant diseases in hospitalized patients and out-patients with elevated ESR; and (ii) the long-term incidence of malignant diseases in patients during 5 years after unsuccessful investigation for elevated ESR. METHODS: A cross-sectional survey was carried out in 128 patients admitted to the Department of General Internal Medicine, University of Kiel and in 94 out-patients under the care of a GP. A retrospective cohort study of 50 patients was also carried out by contacting GPs of patients discharged from hospital after unsuccessful investigation. RESULTS: In the hospitalized patients, the ESR was elevated in 53.1% (68/128) and was normal in 46.9% (60/128). Malignancy was found in 25.0% (17/68) of patients with elevated ESR and in 15% (9/60) of patients with normal ESR (P = 0.16). Of the out-patients, 94 patients with elevated ESR were investigated, of whom 8.5% (8/94) had malignancies (P = 0.004 compared with hospitalized patients). In the follow-up study of 50 patients who had been discharged with the diagnosis "elevated ESR of unknown origin", follow-up information was available from 38 individuals. Of these, 71.0% (27/38) had not developed signs or symptoms of any disease at the time of investigation. Malignant disease had developed in only 5.3% (2/38). CONCLUSION: The prevalence of malignancy in patients with elevated ESR is low, in both the clinical and the general practice setting. Elevation of ESR is not an early sign of malignant disease and does not justify extensive investigation in a patient who has no symptoms which are suggestive of a tumour.

Blood Sedimentation↗
PubMed2002

Morphometry of the corpus callosum in patients with questionable and mild dementia.

Previous studies have shown a reduction in corpus callosum area in advanced Alzheimer's disease, but it is unclear whether callosal atrophy is present in the transitional phase between health and the onset of dementia. The aim of this study was to investigate whether callosal atrophy is present in subjects with questionable and mild dementia and to assess the diagnostic value of callosal measures. In 83 subjects aged 72 to 85 years (33 normal controls, 27 patients with questionable dementia, 23 with mild Alzheimer's disease), magnetic resonance images were recorded and the mid-sagittal callosal area measured. Significant differences were found between normal controls and mild dementia. In subjects with questionable dementia callosal size was intermediate between normal controls and mild Alzheimer's disease. However, callosal measures were unsuitable for diagnostic differentiation between healthy subjects, subjects with questionable dementia, and subjects with mild Alzheimer's disease. The severity of white matter changes did not differ between the groups.

Aged↗
PubMed2001

Impairment of mitogenic activation of peripheral blood lymphocytes in Alzheimer's disease.

Cell-cycle dysregulation might be critically involved in the process of neurodegeneration in Alzheimer's disease (AD). We now provide evidence for a dysfunction of the cell division cycle as a more general cellular phenomenon of the disease. Peripheral blood lymphocytes, stimulated with mitogenic compounds, were less able to express CD69, an early proliferation marker, in AD patients than in age-matched controls. Expression levels of CD69 of both T-cells and B-cells correlated inversely with the Mini-mental Scale. The results suggest that a systemic failure of cellular proliferation control might be of critical importance for the pathomechanism of AD.

Aged↗
PubMed2001

Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer's disease.

Advanced glycation endproducts (AGEs), protein-bound oxidation products of sugars, have been shown to be involved in the pathophysiological processes of Alzheimer's disease (AD). AGEs induce the expression of various pro-inflammatory cytokines and the inducible nitric oxide synthase (iNOS) leading to a state of oxidative stress. AGE modification and resulting crosslinking of protein deposits such as amyloid plaques may contribute to the oxidative stress occurring in AD. The aim of this study was to immunohistochemically compare the localization of AGEs and beta-amyloid (Abeta) with iNOS in the temporal cortex (Area 22) of normal and AD brains. In aged normal individuals as well as early stage AD brains (i.e. no pathological findings in isocortical areas), a few astrocytes showed co-localization of AGE and iNOS in the upper neuronal layers, compared with no astrocytes detected in young controls. In late AD brains, there was a much denser accumulation of astrocytes co-localized with AGE and iNOS in the deeper and particularly upper neuronal layers. Also, numerous neurons with diffuse AGE but not iNOS reactivity and some AGE and iNOS-positive microglia were demonstrated, compared with only a few AGE-reactive neurons and no microglia in controls. Finally, astrocytes co-localized with AGE and iNOS as well as AGE and were found surrounding mature but not diffuse amyloid plaques in the AD brain. Our results show that AGE-positive astrocytes and microglia in the AD brain express iNOS and support the evidence of an AGE-induced oxidative stress occurring in the vicinity of the characteristic lesions of AD. Hence activation of microglia and astrocytes by AGEs with subsequent oxidative stress and cytokine release may be an important progression factor in AD.

Aged↗
PubMed2001

Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer's disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology.

The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the mammalian brain in three different isoforms, two constitutive enzymes (i.e., neuronal, nNOS, and endothelial eNOS) and one inducible enzyme (iNOS). All three isoforms are aberrantly expressed in Alzheimer's disease giving rise to elevated levels of nitric oxide apparently involved in the pathogenesis of this disease by various different mechanisms including oxidative stress and activation of intracellular signalling mechanisms. It still is a matter of debate, however, whether the abnormal expression of NOS isoforms has some primary importance in the pathogenetic chain and might thus be a potential therapeutic target or only reflects a secondary effect that occurs at more advanced stages of the disease process. To tackle this question, we analysed the expression of both eNOS and iNOS in patients with sporadic AD, in transgenic mice expressing human amyloid precursor protein (APP) with the Swedish double mutation under control of the Thy1 promotor (APP23 mice), and after electrolytic cortical lesion in rat, an experimental paradigm associated with elevated expression of APP. In all three conditions, an astrocytosis was induced accompanied by a strong increase of both iNOS and eNOS. Both NOS isoforms were frequently though not always colocalized. Thus, based on the expression pattern of NOS isoforms three types of astrocytes, expressing only one of the two isoforms or both together could be distinguished. In both AD and transgenic mice eNOS-expressing astrocytes exceeded iNOS-expressing astrocytes in number. Astrocytes with elevated levels of iNOS or eNOS were constantly seen in direct association with Abeta-deposits in AD and transgenic mice and were found in the vicinity of the lesion site in the rat cortex. The results of the present study show that expression of both iNOS and eNOS is increased in activated astrocytes under experimental conditions associated with elevated expression of APP (electrolytic brain lesion) or Abeta-deposition (APP23 transgenic mice). Therefore, it is suggested that altered expression of these NOS isoforms being part of AD pathology is secondary to the amyloid pathology and might not be primarily involved in the pathogenetic chain though it might contribute to the maintenance, self-perpetuation and progression of the neurodegenerative process.

Aged↗
PubMed2001

Electron microscopic evidence for different myelination of rat septohippocampal fibres.

Rat septohippocampal fibres are known to originate from GABAergic parvalbumin-containing, fast-firing, fast-conducting neurons and from cholinergic slow-firing, slow-conducting neurons. In the present electron microscopic study, based on immunocytochemical demonstration of parvalbumin and choline acetyltransferase in transverse and horizontal septal sections, it was shown that parvalbumin-immunoreactive fibres are myelinated, but the vast majority of cholinergic fibres are not. As revealed, especially in horizontal sections, the cholinergic axons show considerably finer calibres than parvalbumin-containing ones. These results confirm and extend our previous light microscopic findings. It can be concluded that differences in conduction velocities, presence or absence of myelin sheaths and differences axonal diameters are correlated in the septohippocampal pathway.

Animals↗
PubMed2001

Interferon-gamma is not involved in the intestinal manifestations of the acute murine semiallogenic graft-versus-host disease.

BACKGROUND: The acute murine semiallogenic graft-versus-host disease (GvHD) is known to be associated with Th1 cytokines secreting lymphocytes in the spleen and lymph nodes. However, whether this cytokine secretion pattern is also involved in the intestinal manifestations of acute GvHD (crypt hyperplasia and villous atrophy) is not known, so far. METHODS: We first investigated the secretion of interleukin (IL) 4 (indicative of Th2-type differentiation) and interferon (IFN) 7 (Th1-type differentiation) by splenic and by small bowel lamina propria lymphocytes. In addition, animals were treated with neutralizing antibodies to IL-4 or IL-12. The effect of this treatment on the intestinal morphology was examined. Second, we also investigated the effect of donor-derived IFN-gamma by using donor lymphocytes from IFN-gamma knock-out animals. Third, animals were treated with the fusion protein OX40-Ig which interferes with the OX40-OX40L interaction and thereby inhibits the intestinal manifestations of acute GvHD. RESULTS: We found that, whereas splenic lymphocytes secrete an excess of IFN-gamma, lymphocytes of the intestinal lamina propria secrete less IFN-gamma and IL-4 than control animals. When OX40-Ig is administered to animals with acute GvHD, the intestinal histology normalizes as well as the secretion of IFN-y and IL-4, indicating that the intestinal morphology is not affected by the secretion of IFN-gamma by lamina propria lymphocytes. The treatment of animals suffering from acute GvHD with anti-IL-4 and anti-IL-12, which blocks the differentiation of IFN-gamma secreting T-lymphocytes, did not significantly affect the development of crypt hyperplasia or villous atrophy. Furthermore, donor lymphocytes of IFN-gamma knock-out animals also induced the intestinal manifestations of acute GvHD. CONCLUSIONS: These findings indicate that IFN-gamma is not crucial for the development of crypt hyperplasia and villous atrophy in the murine semiallogenic GvHD.

Animals↗