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Biomedical subjects

T Arendt

Publications and source records attributed to T Arendt.

At least 37 records · Page 2Linked to original sources
PubMed2001

Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization.

Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Alzheimer Disease↗
PubMed2001

Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. I. Mitogen-activated protein kinase cascade.

Alterations in the phosphorylation state of the microtubule-associated protein tau have been associated with the pathogenesis of neurofibrillary degeneration as well as with a neuroprotective action against apoptotic cell death. Mitogen-activated protein kinases (MAPK) phosphorylate tau protein in vitro but the pathophysiological significance of this tau phosphorylation and its effects on neuronal viability is far from clear. Moreover, an in vivo model of activation of MAPK, a key candidate for in vivo tau phosphorylation, is still lacking. The aim of the present study and the accompanying paper was to establish an animal model of stimulated MAPK and to analyse the consequences on tau phosphorylation and the neuronal cytoskeleton. We took advantage of transgenic mice with neurone-specific expression of activated ras protein (p21H-ras(Val12)). The expression of the transgene in these animals is forced to a subset of neurones by the use of the synapsin I promoter. Activity of B-raf was elevated by 37%, while activity of MAPK (ERK1/ERK2) was increased by 25% associated with a subcellular redistribution from the cytoplasmic to the nuclear compartment. Kinases downstream of MAPK such as p90rsk and glycogen synthase kinase 3beta were only marginally affected. Activity of p70S6 kinase was unaltered. The present model might be useful to study the effects of activation of the MAPK cascade on tau phosphorylation and its cell biological sequelae.

Animals↗
PubMed2001

Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. II. Cytoskeletal proteins and dendritic morphology.

In the present study, we analysed changes in the expression, subcellular distribution and phosphorylation state of the microtubule-associated protein tau and other cytoskeletal proteins after neurone-specific activation of the mitogen-activated protein kinase (MAPK) in the CNS in vivo. We used transgenic mice with a neurone-specific expression of activated ras protein (p21H-ras(Val12), synapsin I promoter) that is associated with an augmented activity of the MAPK. Chronic activation of MAPK cascade influenced tau protein phosphorylation, localisation and dendritic morphology. While the amount of tau protein was elevated by 9%, phospho-epitopes detected by the monoclonal antibodies AT270, 12E8 and SMI34 were increased by about 21%, 40% and 59% respectively. Steady-state levels of tau mRNA were not affected. Thus, the increase in tau protein was most likely due to stabilisation of tau protein by augmented phosphorylation. While in wild-type animals tau protein was preferentially localised in axons, a prominent immunoreactivity was found in the somatodendritic compartment of transgenic mice. This subcellular translocation typically seen in pyramidal neurones was associated with an increase in the dendritic calibre by about 30% and is paralleled by an increase in tubulin of 19%. We were unable to obtain any morphological indication of neurodegenerative processes in these animals. We suggest that the moderate increase in tau protein and phosphorylation may be part of the neuroprotective mechanism. However, further studies on aged transgenic mice will be necessary to establish potential effects on neuronal viability.

Animals↗
PubMed2001

Perineuronal nets in the rhesus monkey and human basal forebrain including basal ganglia.

Perineuronal nets of extracellular matrix have been shown to characterize the microenvironment of individual neurons and the chemoarchitecture of brain regions such as basal forebrain nuclei. Previous work has also demonstrated that neurons in the human cerebral cortex ensheathed by perineuronal nets rarely undergo cytoskeletal changes in Alzheimer's disease, suggesting a neuroprotective effect of extracellular matrix components. It is not known, however, whether or not perineuronal nets are absent in the microenvironment of the cholinergic basal forebrain neurons that are involved early in the cascade of neurodegeneration in humans. Therefore, the present study was undertaken to examine the distribution patterns of perineuronal nets in the basal forebrain of the higher primates, rhesus monkey and human. Cytochemical staining was performed with the lectin Wisteria floribunda agglutinin and a polyclonal antibody to core proteins of chondroitin sulfate proteoglycans in the perfusion-fixed tissue of rhesus monkeys. In human brains, perineuronal nets were only stained with the immunoreaction for chondroitin sulfate proteoglycans. The results showed similar characteristics in distribution patterns of perineuronal nets in the medial septum, the diagonal band of Broca, the basal nucleus of Meynert (Ch1-Ch4), the lateral septum, the caudate-putamen, and the globus pallidus in both species. Double-labelling revealed that the vast majority of cholinergic neurons, labelled either with antibodies to choline acetyltransferase or the low-affinity neurotrophin receptor p75(NTR), were not ensheathed by perineuronal nets. A small subpopulation of net-associated neurons in close proximity to or intermingled with cholinergic neurons of the Ch1-Ch4 cell groups was found to be immunoreactive for parvalbumin. In the caudate-putamen, a large number of the parvalbumin-positive neurons were surrounded by perineuronal nets, whereas in the external and internal segments of the globus pallidus the coincidence of both markers was nearly complete. The study demonstrates that perineuronal nets of extracellular matrix are associated with different types of non-cholinergic neurons in the primate basal forebrain. The absence of nets around cholinergic basal forebrain neurons may be related to their slow modulatory activity but may also contribute to their susceptibility to degeneration in Alzheimer's disease.

Acetylcholine↗
PubMed2001

Disturbance of neuronal plasticity is a critical pathogenetic event in Alzheimer's disease.

Brain areas affected by AD pathology are primarily those structures that are invovled in the regulation of "higher brain functions". The functions these areas subserve such as learning, memory, perception, self-awareness, and consciousness require a life-long re-fittng of synaptic contacts that allows for the acquistion of new epigenetic information, a process based on a particularly high degree of structural plasticity. Here, we outline a hypothesis that it is the "labile state fo differentiation" of a subset of neurons in the adult brain that allows for ongoing neuroplastic processes after development is completed but at the same time renders these neurons particularly vulnerable. Mechanisms of molecular and cellular control of neuronal differentiation and proliferation might, thus, not only play a role during development but critically involved in the pathogenesis of neurodegeneration.

Alzheimer Disease↗
PubMed2001

Immunofluorescence and immunoelectron microscopic evidence for differences in myelination of GABAergic and cholinergic septohippocampal fibres.

It is known that the rat septohippocampal projection is realised at least by GABAergic, parvalbumin containing and cholinergic fibres. The GABAergic component originates from fast-firing and fast-conducting neurons, whereas the cholinergic component represents the slow-firing, slow-conducting type. The present immunofluorescence and immunoelectron microscopic study shows that the vast majority of parvalbumin-immunoreactive, GABAergic axons are surrounded by enormously thick myelin sheaths, but choline acetyltransferase immunoreactive axons were rarely found to be myelinated. In addition, cholinergic fibres show considerably smaller diameters. Accordingly, our results are correlated with the well-known differences in conduction velocities between the GABAergic and cholinergic fibres of the septohippocampal pathway, which depend on myelination and axon calibre.

Acetylcholine↗
PubMed2001

Expression and distribution of the prolactin receptor in normal rat liver and in experimental liver cirrhosis.

Recent results have suggested a role for prolactin (PRL) as a regeneration factor in the liver. In order to investigate the involvement of prolactin in the pathogenesis of liver cirrhosis, we studied the expression of the prolactin receptor (PRLR) and PRL during the development of cirrhosis in an animal model. 30 male rats were exposed to CCl4 by inhalation. Phenobarbitone was added to the drinking water to accelerate the formation of toxic metabolites by enzyme induction. Two control groups of 30 animals each were treated with phenobarbitone only or received no treatment. 10 animals of each group were sacrificed 35, 55, and 70 days after initiation of treatment. Liver tissue was subjected to histological examination, which demonstrated fibrosis of different grades and cirrhosis in the CCl4-treated rats. Expression of PRLR mRNA was investigated by mRNA extraction, RT-PCR and computer-supported densitometric evaluation. Compared to control liver, PRLR mRNA was expressed at a higher level in fibrotic and cirrhotic liver specimens. In normal tissue, immunohistochemical staining showed a high concentration of PRLR around the central vein and in the epithelium of the bile ducts. This pattern of distribution was lost in fibrosis and cirrhosis. An accumulation of PRLR was demonstrated within the damaged cells. Neither PRL nor PRL mRNA was detectable in normal, fibrotic, or cirrhotic liver. We conclude that PRLR is distributed in normal rat liver in a typical pattern which is lost with increasing fibrosis. PRL is not produced by rat liver, indicating that PRL does not act through autocrine or paracrine mechanisms.

Animals↗
PubMed2001

Correlation between cortical theta activity and hippocampal volumes in health, mild cognitive impairment, and mild dementia.

Cognitive decline is known to be associated with both increased theta power over frontal regions and hippocampal atrophy. The aim of this study was to reveal the relation between these parameters in groups with mild dementia, mild cognitive impairment, and healthy control subjects. The authors examined a preliminary randomly selected sample of 39 right-handed subjects joining the Leipzig Longitudinal Study of the Aged, consisting of 17 normal elderly subjects, 12 patients with mild cognitive impairment, and 10 patients with mild dementia assessed by Clinical Dementia Rating. All subjects were between 75 and 85 years old (mean age, 78 years; standard deviation, 2.78 years) and underwent EEG and brain MRI. Mean spectral power densities were calculated, and hippocampal body volume was measured. Significant negative linear correlations between theta power over frontal regions and hippocampal volumes were found. The results support the assumption about a relationship between hippocampal atrophy and theta power, and may be helpful for a better understanding of the course of Alzheimer's disease.

Aged↗
PubMed2000

Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration.

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Different myelination of rat septohippocampal fibres as revealed by immunofluorescence double-labelling.

The present study focuses on the myelination of rat septohippocampal fibres that are known to originate from GABAergic parvalbumin-containing, fast-firing, fast-conducting neurons and from cholinergic slow-firing, slow-conducting neurons. With the combined immunofluorescence for parvalbumin/myelin basic protein and choline acetyltransferase/myelin basic protein it was shown that the vast majority of parvalbumin-containing fibres are myelinated, but the choline acetyltransferase-containing fibres are not. Accordingly, our results confirm the expectation that conduction velocities and presence or absence of myelin sheaths are also correlated in the septohippocampal pathway.

Animals↗
PubMed2000

Increase in vulnerability of middle-aged rat brain to lead by cerebral energy depletion.

The neurotoxic effects of low-level lead (Pb) during senescence are increasing interests of importance. We investigated the effects of low-level Pb on the brain in a normal condition and a pathophysiological condition of energy shortage that is commonly found in age-related neurological diseases. Middle-aged rats (15 months old) were exposed to 200 mg/l Pb acetate in drinking water for 2 months and thereafter received bilateral intracerebroventricular injections of streptozotocin (STZ). After 1 month's additional exposure to the same level of Pb solution as before the rats were sacrificed. Blood and brain Pb levels were measured by graphite furnace atomic absorption spectrophotometry. Energy-rich phosphate levels in the brain were determined by high-performance liquid chromatography equipped with a UV detector. Astroglial activation and glucose-regulated protein (GRP)94 expression were examined immunohistochemically. Exposure to Pb increased the blood Pb level to 10.8 microg/dl and the brain Pb level to 0.052 microg/g. But a significant additional increase in the brain Pb level, to 0.101 microg/g, became obvious in rats treated with Pb + STZ. Both Pb and STZ induced perturbation in brain energy metabolism, but no further alteration in energy metabolite levels was found in rats treated with Pb + STZ. Astroglial activation and GRP94-positive astrocytes and neurons were found only in the brains of Pb + STZ-treated rats. These results suggest that exposure to low-level Pb can perturb brain energy metabolism and the brain becomes more vulnerable to Pb when it is under energy stress.

Adenosine Diphosphate↗
PubMed2000

The core-shell dichotomy of nucleus accumbens in the rhesus monkey as revealed by double-immunofluorescence and morphology of cholinergic interneurons.

Double-immunolabelling experiments for the combinations, calretinin (CR)-calbindin, CR-tyrosine hydroxylase (TH) and calbindin-TH, were performed in rhesus monkeys to compare the chemical organization of the nucleus accumbens (ACC) in primates and rodents. Additionally, the soma sizes and numbers of primary dendrites of cholinergic neurons in the subregions of ACC were compared with those of caudate-putamen. Our findings subserve the shell-core concept also in the primate ACC, as like in the rat, CR immunoreactivity (-ir) due to intense neuropil labelling is very strong in the shell of rhesus monkey, but poor in the core. The staining intensity of this marker decreases in dorsoventral direction. An almost complementary pattern was noted in sections of the monkey ACC immunostained for both calbindin and TH. The cholinergic interneurons of the nucleus caudatus-putamen are clearly distinguished from those of the ACC and insula Calleja magna by their much bigger soma sizes and higher numbers of primary dendrites. Cholinergic neurons of the shell were found to be slightly, but significantly, larger than those of the core that also subserves subdivision of the primate ACC into shell and core. A low proportion of tyrosine-hydroxylase-immunostained cells, already previously described below the rostral ACC, co-expressed CR but not calbindin. A CR-immunoreactive neuronal population, intermingled with these cells, extends as a stripe medially to the ACC along the septal part of corpus callosum into the lateral septal area. The presumed origin of CR-immunoreactive fibres in the shell of ACC is discussed.

Acetylcholine↗
PubMed2000

[Effect of exercise tolerance test on hemostasis in patients with and without coronary heart disease].

BACKGROUND: Physical exercise leads to an elevated coagulation activity with a possibly disturbed hemostatic balance. Therefore patients with coronary heart disease have a potentially increased risk of thromboembolic events after a bicycle exercise tolerance test, that is frequently performed for diagnostic reasons. PATIENTS AND METHODS: Patients with angiographically known coronary heart disease (Group I: n = 49; age 59 years; male = 42, female = 7) were investigated in comparison to a healthy cohort (Group 2: n = 51; age 53 years; male = 44, female = 7) to study the influence of a standardized exercise tolerance test on hemostatic variables. Blood samples were taken before and after exercise. RESULTS: No significant changes were found for any investigated parameter between both groups. However, 3 parameters did change significantly within the groups: factor VIII rose in Group 1 from 132 to 156% and in Group 2 from 106 to 136% and the von Willebrand factor rose in Group 1 from 230 to 249% and in Group 2 from 228 to 247%. An elevated fibrinolytic potential was found with an increase of plasminogen-alpha 2-antiplasmin in Group 1 from 251 to 401 micrograms/l and in Group 2 from 247 to 350 micrograms/l. CONCLUSION: The findings underline the clinical presumption that exercise tolerance test does not increase the risk for thromboembolic complications in patients with coronary heart disease in comparison to patients without coronary heart disease, as long as the exercise tolerance test is performed in a standardized way and under aerobe conditions.

Antifibrinolytic Agents↗
PubMed2000

Aberrant expression of nNOS in pyramidal neurons in Alzheimer's disease is highly co-localized with p21ras and p16INK4a.

Aberrancies of growth and proliferation-regulating mechanisms might be critically involved in the processes of neurodegeneration in Alzheimer's disease (AD). Expression of p21ras and further downstream signalling elements involved in regulation of proliferation and differentiation as, for example, MEK, ERK1/2, cyclins, cyclin-dependent kinases and their inhibitors such as those of the p16INK4a family, are elevated early during the course of neurodegeneration. Activation of p21ras can also directly be triggered by nitric oxide (NO), synthesized in the brain by various isoforms of nitric oxide synthase (NOS) that might be differentially involved into the pathomechanism of AD. To study the potential link of NO and critical regulators of cellular proliferation and differentiation in the process of neurofibrillary degeneration, we analyzed the expression pattern of NOS-isoforms, p21ras and p16INK4a compared to neurofibrillary degeneration in AD. Additionally to its expression in a subtype of cortical interneurons that contain the nNOS-isoform also in normal brain, nNOS was detected in pyramidal neurons containing neurofibrillary tangles or were even unaffected by neurofibrillary degeneration. Expression of nNOS in these neurons was highly co-localized with p21ras and p16INK4a. Because endogenous NO can activate p21ras in the same cell which in turn leads to cellular activation and stimulation of NOS expression [H.M. Lander, J.S. Ogiste, S.F.A. Pearce, R. Levi, A. Novogrodsky, Nitric oxide-stimulated guanine nucleotide exchange on p21 ras, J. Biol. Chem. 270 (1995) 7017-7020], the high level of co-expression of NOS and p21ras in neurons vulnerable to neurofibrillary degeneration early in the course of AD thus provides the basis for an autocrine feedback mechanism that might exacerbate the progression of neurodegeneration in a self-propagating manner.

Aged↗
PubMed2000

Abnormally phosphorylated protein tau in the cortex of aged individuals of various mammalian orders.

Aged individuals of mammalian species displaying hyperphosphorylated tau protein may be suitable natural models for investigating neurodegenerative alterations occurring, for example, in Alzheimer's disease. Therefore, autoptic tissue from the entorhinal, motor and prefrontal cortices of 14 mammalian species was screened using the monoclonal antibody AT8, which is directed against a phosphorylated epitope of human tau and applicable to the tissues of aged domestic animals, as shown in previous studies. AT8-immunoreactive neuronal processes and perikarya were revealed in Campbell's guenon, rhesus monkey, baboon, rabbit, spectacled bear, guanaco, reindeer and bison. Signs for considerable neuropathological alterations in aged bisons also included neuropil threads, whereas AT8 immunoreactivity in the other species was only sparsely scattered. Hyperphosphorylated tau in the brain of an 28-year-old rhesus monkey was also detected by AT100, PHF-1 and TG-3 antibodies, but only in the hippocampal formation and entorhinal cortex, which are known as starting point for tangle spreading in the cortex of Alzheimer patients.

Aging↗
PubMed2000

Modulation of APP processing and secretion by okadaic acid in primary guinea pig neurons.

Primary cultures of guinea pig neurons were used as a model system to study the influence of the protein phosphatase inhibitor okadaic acid (OA) on the secretion, processing and phosphorylation of the amyloid precursor protein (APP). This primary cell culture system mimics more closely than other cell culture systems the human in vivo condition, as guinea pig APP is 98% homologous to human APP at the protein level, identical regarding the Abeta sequence and is processed in a similar manner as human APP. Both intracellular and secreted APP was upregulated by OA treatment (0.3 nM-10 nM) of 14 days old cultures in a concentration dependent manner while the amount of Abeta in the medium was decreased. OA treatment did not affect cell membrane integrity of primary neurons but induced DNA fragmentation. Phosphorylation of APP was unchanged by the low OA concentration used. These results show that OA treatment of guinea pig primary cultures might be used as a model to study the effects of modulation of signal transduction on secretion and processing of APP.

Amyloid beta-Peptides↗