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T Arendt

Publications and source records attributed to T Arendt.

At least 109 records · Page 6Linked to original sources
PubMed1995

Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury--II. Reactive expression of the nerve growth factor gene in astrocytes.

Long-term consumption of ethanol both in human and rodent induces a process of chronic degeneration of cholinergic basal forebrain neurons which results in a cholinergic deafferentation of the cortical mantle. We have used quantitative northern blot analysis and in situ hybridization to demonstrate that these degenerative events in rat evoke an increase in the expression of the nerve growth factor gene in a number of brain areas, including the cholinergic basal forebrain nuclei and their cortical target regions. By combining non-radioactive in situ hybridization and immunohistochemistry activated astrocytes were identified as the major source of altered nerve growth factor gene expression. This increased nerve growth factor expression is paralleled by a dendritic remodelling of basal forebrain neurons, while the expression of choline acetyltransferase in surviving neurons remains the same. This failure of nerve growth factor to rescue the expression of choline acetyltransferase differs from the effects of exogenously administered nerve growth factor in acutely lesioned systems. The results indicate that under certain conditions of chronic neurodegeneration, the utilization of nerve growth factor might be impaired, which could be due to a defective nerve growth factor signalling mechanism.

Alcohol Drinking↗
PubMed1995

Degeneration of rat cholinergic basal forebrain neurons and reactive changes in nerve growth factor expression after chronic neurotoxic injury--I. Degeneration and plastic response of basal forebrain neurons.

The process of degeneration and dendritic reorganization of cholinergic neurons was investigated in the rat basal forebrain under the conditions of chronic neurotoxic injury induced by long-term consumption of ethanol. After 28 weeks of ethanol treatment (20% v/v), both the number of choline acetyltransferase-immunoreactive basal forebrain neurons and levels of biochemical measures of cholinergic neurons, such as the activity of choline acetyltransferase and the synthesis and content of acetylcholine, were decreased by about 60-80%. The number of cholinergic neurons showing a positive hybridization signal to choline acetyltransferase messenger RNA was decreased to a similar extent. On the contrary, the reduction in the number of neurons immunoreactive for nerve growth factor receptor p75, which in control brains is highly co-localized with the expression of choline acetyltransferase, was much less pronounced and reached only 20-30%. The loss of choline acetyltransferase expression was associated with a cellular hypertrophy. Neurons which had survived the neurotoxic damage, furthermore, showed a remodelling of the dendritic organization which was quantitatively investigated after Golgi impregnation. This process of dendritic reorganization was mainly characterized by an increase in number and length of terminal dendritic segments. The results indicate that under the conditions of the present paradigm of chronic neurodegeneration, a certain number of cholinergic neurons persists in a form where they lost their ability to express detectable amounts of choline acetyltransferase messenger RNA and the enzyme protein. Persisting neurons, however, show both expression of nerve growth factor receptor p75 and signs of perikaryal and dendritic growth. It might, therefore, be hypothesized that chronic degeneration of cholinergic basal forebrain neurons triggers reactive attempts of repair which involve the action of trophic factors such as nerve growth factor.

Alcohol Drinking↗
PubMed1995

Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer's disease.

The sequential activation of the mitogen-activated protein kinase kinase and its substrate, the mitogen-activated protein kinase is involved in a cascade of protein kinases which link a number of cell surface signals to intracellular changes in enzyme activity and gene expression. In vitro, mitogen-activated protein kinase is able to phosphorylate the microtubule-associated protein tau at Ser-Pro and Thr-Pro sites, thereby generating abnormally hyperphosphorylated tau species that are similar to paired helical filament-tau found in Alzheimer's disease. In the present study, we analysed the levels of immunoreactive mitogen-activated protein kinase kinase and mitogen-activated protein kinase in the temporal cortex (area 22) of patients with Alzheimer's disease by means of enzyme-linked immuno-sorbent assays and compared these changes with the content of abnormally phosphorylated paired helical filament-tau. The levels of immunochemically detected mitogen-activated protein kinase kinase and mitogen-activated protein kinase were both increased in Alzheimer's disease by between 35 and 40% compared with age-matched controls. Elevation of mitogen-activated protein kinase kinase was most pronounced during early stages of Alzheimer's disease and was inversely related to the tissue content of abnormally phosphorylated paired helical filament-tau. Pronounced immunoreactivity of mitogen-activated protein kinase kinase and mitogen-activated protein kinase was present in both tangle bearing neurons and unaffected neurons of the temporal cortex. Immunoreactive neurons were most often localized in the direct vicinity of neuritic plaques. In Alzheimer's disease, the subcellular distribution of mitogen-activated protein kinase kinase and mitogen-activated protein kinase showed a striking translocation from the cytoplasmic to the nuclear compartment. It is suggested that the activation of the mitogen-activated protein kinase cascade which appears to be an early feature of Alzheimer's disease might be critically involved in self-stimulating processes of neurodegeneration and aberrant repair under these conditions.

Aged↗
PubMed1995

Paired helical filament-like phosphorylation of tau, deposition of beta/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A.

Alzheimer's disease is histopathologically characterized by neurofibrillary tangles, formed by the abnormally high phosphorylated tau protein, and senile plaques which largely consist of the beta/A4-amyloid peptide. Metabolism of the amyloid precursor protein and its processing into beta/A4-amyloid is regulated by protein phosphorylation. Thus, an imbalance between protein phosphorylation and dephosphorylation might be crucial for the development of the molecular hallmarks of Alzheimer's disease. We report here that chronic infusion into rat brain ventricles of okadaic acid, a specific inhibitor of the serine/threonine protein phosphatases 1 and 2A, results in a severe memory impairment, accompanied by a paired helical filament-like phosphorylation of tau protein and the formation of beta/A4-amyloid containing plaque-like structures in gray and white matter areas.

Amyloid beta-Peptides↗
PubMed1994

In vivo phosphorylation in the rat basal nucleus induces PHF-like and APP immunoreactivity.

In vivo phosphorylation was stimulated in the rat basal nucleus by stereotaxic injection of the phosphatase inhibitor okadaic acid (OA). Hyperphosphorylation of neurofilaments and of the microtubule-associated proteins tau and MAP2 was associated with their redistribution from the axonal compartment into the cell bodies of large projection neurones where they appeared as paired helical filament (PHF)-like immunoreactivity. Astrocytes showed a dramatic increase in APP immunoreactivity and changed their appearance to a stellate shape with long processes. The results demonstrate that abnormal tau phosphorylation and changes in the expression and/or metabolism of APP can be induced in vivo by altering protein phosphorylation. The present experimental paradigm might, therefore, provide a useful tool to model early steps of the pathomechanism of Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Digoxigenin-tagged anti-GFAP and multiple labelling of human glia, vessels and beta-amyloid.

Cytochemical procedures for the combined demonstration of astroglia, microglia, blood vessels and beta-amyloid in the human brain were developed. These multiple label experiments include the first adaptation of the digoxigenin-antidigoxigenin technique to immunocytochemistry by using digoxigenylated antibodies directed against the glial fibrillary acidic protein and its visualization in astrocytes with an antidigoxigenin-peroxidase conjugate and diaminobenzidine as chromogen. Furthermore, the specific labelling of microglial cells was performed with the novel enhanced polymer one-step staining technique, non-interfering with conventional detection systems. The demonstration of spatial relationships between glial and vascular components in normal tissue and their alterations, e.g. in Alzheimer's disease, might provide insights into the time course and localization of pathological events.

Alzheimer Disease↗
PubMed1994

Impairment in memory function and neurodegenerative changes in the cholinergic basal forebrain system induced by chronic intake of ethanol.

Chronic intake of ethanol both in human and rat results in a substantial impairment in memory function associated with a reduction in the number of cholinergic neurons in the basal forebrain which give rise to the cholinergic afferentation of the cortical mantle. Degenerative changes in the basal forebrain are paralleled by the concomitant reduction of presynaptic cholinergic markers (synthesis, content and release of acetylcholine) in the neocortex and hippocampus. Cognitive dysfunction in rat induced by ethanol treatment can be ameliorated by the pharmacological manipulation of central cholinergic neurotransmission by physostigmine, arecoline or nicotine. Furthermore, fetal brain transplants rich in cholinergic neurons are able to restore cognitive function which argues in favour of a cholinergic aspect of alcohol-induced behavioural dysfunction. The observation, that implantation of purified astrocytes results in a similar restoration of learning and memory abilities associated with a recovery of cholinergic function, further indicates that behavioural sequelae of alcohol intake can largely be ameliorated by a trophic stimulation directed towards the cholinergic basal forebrain system. Regarding the cholinergic basal forebrain system as a component of the ascending reticular activation system, the involvement of the cholinergic afferentation of the cortical mantle in the mediation of memory processes and their dysfunction under neurodegenerative conditions can be explained on the basis of the "Hippocampal Memory Indexing Theory" of Teyler and DiScenna. The hypothesis is formulated in the present paper that mental dysfunction observed after chronic ethanol consumption can largely be attributed to a degeneration of the cholinergic pathway of the ascending activation system resulting in an impairment of cortical activation, clinically appearing as the "syndrome of partial cholinergic deafferentation of the cortical mantle".

Acetylcholine↗
PubMed1994

Pancreatic duct mucosa following bile salt injury in cats. Morphology, barrier function to pancreatic exocrine proteins and vulnerability by activated pancreatic juice.

We studied pancreatic duct mucosal morphology and barrier function to both activated and nonactivated pancreatic exocrine proteins following bile salt injury in cats. Prograde pancreatic duct perfusion with 15 mM glycodeoxycholate caused epithelial disruption with focal epithelial loss in the majority of animals. In these cats, flow of preanalyzed nonactivated rat pancreatic juice along the duct resulted in a selective loss of zymogens from the duct lumen as determined by two-dimensional isoelectric focusing-sodium dodecyl sulfate gel electrophoresis and reversed-phase high-performance liquid chromatography. Proteins lost had a low isoelectric point (< or = 5.7) and a molecular weight as large as 47,000 Da and included chymotrypsinogen 1, trypsinogens 1 and 2, and procarboxypeptidases B. Proteins with a high isoelectric point (> 5.7), a high molecular weight (> 47,000 Da), or both, were completely recovered from the duct lumen. Flow of activated rat pancreatic juice along a pancreatic duct with bile salt-induced epithelial disruptions caused additional morphologic alterations including an increase in epithelial destruction and occasional necrosis of the duct interstitial and vascular tissue. In some cats, in which the integrity of the ductal epithelium remained preserved following exposure to the bile salt, neither loss of rat pancreatic exocrine zymogens from the duct lumen nor degradation of the duct mucosa by activated rat pancreatic juice was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Abnormally phosphorylated tau protein in Alzheimer's disease: heterogeneity of individual regional distribution and relationship to clinical severity.

The distribution of abnormally phosphorylated tau proteins was investigated in a number of cortical areas and in the basal nucleus of Meynert of 12 patients with Alzheimer's disease. Quantification was performed with a sensitive sandwich enzyme-linked immunosorbent assay employing the monoclonal antibody B5-2, which immunoreacts with neurofibrillary tangles, dystrophic neurites surrounding amyloid cores of plaques and neuropil threads. On western blots, the monoclonal antibody B5-2 specifically labels the abnormally phosphorylated paired helical filament-tau species in a phosphorylation-dependent manner but is not cross-reactive to normal tau proteins. The preferential involvement of cytoarchitecturally defined cortical areas showed marked individual differences in Alzheimer's disease, and no unique distribution pattern of abnormally phosphorylated tau proteins could be established. While regional heterogeneities along the rostrocaudal extension of the brain declined with the progression of the disease, lateral differences which were largely non-directional appeared to be more stable over time. The mean content of abnormally phosphorylated tau proteins of individual cases was significantly related to the severity of the disease. On a regional scale, this correlation was highest for the basal nucleus. The formation of abnormally phosphorylated tau was associated with a loss of normal soluble tau proteins. Those cortical areas which in normal brain showed the highest amount of normal soluble tau proteins appeared to be particularly prone to deposition of abnormally phosphorylated tau proteins. The present results indicate that the formation of abnormally phosphorylated tau proteins can be initiated in the neuropil at more than one brain area. The spreading of the pathology appears to involve both intracortical and subcortical pathways but largely spares interhemispheric pathways. It is hypothesized that regional differences in the compartmentation and metabolism of tau proteins might reflect the molecular basis for the regionally different vulnerability in Alzheimer's disease.

Adult↗
PubMed1994

Bile induced acute oedematous pancreatitis in rats: non-parallel changes in pancreatic morphology and amylase release in vitro.

Pancreatic morphology and amylase release from isolated pancreatic acini in response to caerulein was studied in the course of an experimental bile induced acute pancreatitis without acinar necrosis. The inflammation was induced by retrograde microinfusion of 25 microliters bile into the rat bile pancreatic duct. A dissociation between functional and structural findings was seen. One hour after the bile injury, there was a transient change in acinar cell function. The response to stimulation by caerulein was reduced by 50%, whereas the sensitivity to caerulein was normal. There was oedema and an initial leucocyte infiltration of the gland. Six hours, one day, three days, and seven days after the bile injury, there was an acute interstitial oedematous pancreatitis with a modest polymorphonuclear leucocyte infiltration of the interstitium and widespread acinar vacuolisation. Morphological changes were most pronounced at the third postoperative day. Acinar amylase release, however, was normal both in terms of sensitivity and responsiveness to stimulation. These results show that bile injury may result in an initial disturbance of acinar cell function. Normal acinar amylase release prevailing in the course of the inflammation suggests that disturbance of the acinar amylase secretory response is not a primary stimulant of the inflammation before the development of acinar necrosis.

Amylases↗
PubMed1993

Bile-induced acute pancreatitis in cats. Roles of bile, bacteria, and pancreatic duct pressure.

The relationship between pancreatic duct pressure, bile, bacterial infection of bile, and the development of acute pancreatitis was studied in a feline model. The cat main pancreatic duct was perfused from the head to the tail of the gland with bile and/or Escherichia coli bacteria at "basal" pancreatic duct pressure (< 10 cm H2O) and at pancreatic duct pressure in the upper physiologic range (45 cm H2O). Sterile bile and sterile control solution produced no inflammatory alterations at either pressure. Infected control solution caused a mild acute edematous pancreatitis under low and high pressure. Infected bile caused a severe acute edematous pancreatitis at basal duct pressure; at high pressure, additional focal acinar necrosis was observed in the majority of animals. Infected bile was found to raise basal pancreatic duct pressure by 30%. The other test solutions, which caused only mild inflammatory alterations of the pancreas, did not alter duct pressure. We conclude: (1) Bacterial infection is important for the initiation of acute pancreatitis in this model. (2) High physiologic duct pressure may result in the conversion of nondestructive forms of the inflammation to acinar necrosis. (3) Infected bile-induced increase in duct pressure is likely to result from compression of the duct lumen by the inflammatory edema of the gland.

Acute Disease↗
PubMed1992

Perisomatic sprouts immunoreactive for nerve growth factor receptor and neurofibrillary degeneration affect different neuronal populations in the basal nucleus in patients with Alzheimer's disease.

Aberrant morphological profiles, most likely reflecting a process of perisomatic sprouting, have been detected in Alzheimer's disease (AD) on neurons of the basal nucleus of Meynert by means of Golgi impregnation. Using the mouse monoclonal antibody, ME 20.4., perisomatic profiles were shown to be immunoreactive for nerve growth factor receptor (NGFR). Double label studies using either thioflavin S or anti-neurofibrillary tangle (NFT) antibody B5 in combination with ME 20.4 demonstrated that neurons with aberrant growth profiles failed to express neurofibrillary tangle-bearing material, which otherwise could be detected in large amounts throughout the basal forebrain. The results indicate that in AD, neurons in the basal forebrain, not affected by neurofibrillary degeneration, respond to an increased trophic influence. Dendritic sprouting in AD might, therefore, more likely be regarded as an attempt by the nervous system to repair itself following damage rather than as an abnormal process with primary pathologic significance leading to cellular degeneration.

Aged↗
PubMed1992

Intracortical grafts of purified astrocytes ameliorate memory deficits in rat induced by chronic treatment with ethanol.

Chronic intake of ethanol in rat results in a substantial and permanent impairment in memory function which can be ameliorated by intracortical grafting of fetal tissue derived from the primordial basal forebrain. The present study demonstrates that grafting of purified astrocytes is equally effective in improving the performance in the eight-arm radial maze. In comparison, the rate of behavioral recovery is even more accelerated after grafting of astrocytes than after fetal basal forebrain transplants. The improvement in memory function can be detected as early as 2 weeks after operation and is accompanied by an increase in the activity of choline acetyltransferase in the basal forebrain previously reduced after ethanol treatment. Graft-induced behavioral recovery in the present paradigm is most likely due to a neurotrophic influence of astrocytes mediated via the cholinergic basal forebrain system.

Animals↗
PubMed1992

Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development--a study of molecular forms.

The pattern of molecular forms of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) separated by density gradient centrifugation was investigated in the brain and cerebrospinal fluid in Alzheimer's disease (AD), in human embryonic brain and in rat brain after experimental cholinergic deafferentation of the cerebral cortex. While a selective loss of the AChE G4 form was a rather constant finding in AD, a small but significant increase of G1 for both AChE and BChE was found in the most severely affected cases. Both in normal human brain and in AD a significant relationship could be established between the AChE G4/G1 ratio in different brain regions and the activity of choline acetyltransferase (ChAT). A similar decrease of the AChE G4 form as observed in AD can be induced in rat by experimental cholinergic deafferentation of the cerebral cortex. The increase in G1 of both AChE and BChE in different brain regions in AD is quantitatively related to the local density of neuritic plaques which are histochemically reactive for both enzymes. In human embryonic brain, a high abundance of G1 and a low G4/G1 ratio for both AChE and BChE was found resembling the pattern observed in AD. Furthermore, both in embryonic brain and in AD AChE shows no substrate inhibition which is a constant feature of the enzyme in the adult human brain. It is, therefore, concluded that the degeneration of the cholinergic cortical afferentation in AD as reflected by a decrease of AChE G4 is accompanied by the process of a neuritic sprouting response involved in plaque formation which is probably associated with the expression of a developmental form of the enzyme.

Acetylcholinesterase↗
PubMed1991

The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats.

Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.

Acetylcholine↗
PubMed1991

Penetration of lanthanum through the main pancreatic duct epithelium in cats following exposure to infected human bile.

The main pancreatic duct epithelium acts as a barrier to the diffusion of molecules from the duct lumen into pancreatic acinar and interstitial tissue. We studied sequential ultrastructural characteristics of the loss of epithelial barrier function in the cat using lanthanum, an electron-opaque tracer, following perfusion of the duct from the tail to the duodenum with infected human bile. Tight junctions between duct epithelial cells were found to become permeable to the tracer as early as after 15 min of exposure. Later, there was progressive disintegration of intercellular junctions and epithelial loss. Lanthanum penetrated the duct epithelium exclusively on an intercellular path. Loss of barrier function of the pancreatic duct epithelium was consistently associated with subsequent development of acute interstitial edematous pancreatitis. There was no association between the degree of duct epithelial damage and the severity of acute pancreatitis. Both bile and a suspension of bacteria alone were not harmful to the pancreas. Sequential perfusion produced acute pancreatitis only when at first bile and then the bacterial suspension was perfused. A reversed succession of perfusates produced no morphologic alterations. We conclude: (1) Increased tight junction permeability is an early lesion in acute bile-induced pancreatitis: (2) loss of duct epithelial barrier function is important for the initiation but not for the severity of the inflammation; and (3) bile renders duct epithelial intercellular junctions vulnerable to Escherichia coli bacteria.

Acute Disease↗
PubMed1991

[Syndrome of partial cholinergic deafferentation of the cortical mantle--a concept for describing the brain-behavior relationship in dementia diseases].

The identification of morphological and biochemical changes in neurodegenerative disorders with both common and different patterns of neuropsychological dysfunction may help to define the neurobiological substrate of amnesic and dementing disorders, and, furthermore, will give some insight into the neuronal organisation of memory processes. The concept of "subcortical and cortical dementia" and the "cholinergic hypothesis of memory dysfunction" reflect two different theoretical approaches which relate psychopathological disturbances in Alzheimer's disease, Parkinson's disease, Korsakoff's psychosis and related conditions either to structurally or to chemically defined systems of the brain. In order to overcome limitations arising from this dichotomy of structural and chemical approaches to the brain-behaviour-relationship, the concept of a "syndrome of partial cholinergic deafferentation of the cortical mantle" is suggested in the present paper. This concept is supported by evidence derived from the biochemical, morphological and behavioural sequelae of acute and chronic experimental interference with the cholinergic afferentation of the cortical mantle by the application of neurotoxins, by pharmacological intervention and by neurotransplantation in rat. Regarding the cholinergic projection neurons of the basal forebrain and upper brainstem as components of the reticular activating system, the involvement of the cholinergic afferentation of the cortical mantle in the mediation of memory processes and their dysfunction under the conditions of neurodegenerative disorders can be explained on the basis of the "Hippocampal Memory Indexing Theory" of Teyler and DiScenna.

Afferent Pathways↗