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Biomedical subjects

E N Steur

Publications and source records attributed to E N Steur.

11 recordsLinked to original sources
PubMed2001

alpha-synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei.

Advanced silver stains and immunohistochemical reactions against alpha-synuclein were used to detect Parkinson's disease-related cytoskeletal abnormalities in select lower brain stem nuclei. Various types of inclusion bodies including inconspicuous and heretofore unnoted granular particles and thread-like Lewy neurites were visualized. Of the nuclei investigated (gigantocellular reticular nucleus, bulbar raphe nuclei, coeruleus-subcoeruleus area), only lipofuscin- or neuromelanin-laden neuronal types showed a propensity to develop the pathological changes. Neuronal types devoid of pigment deposits remained free of the cytoskeletal abnormalities. Fine, dust-like particles and small globular Lewy bodies were encountered solely within the limits of intraneuronal lipofuscin or neuromelanin deposits.

Aged↗
PubMed2001

Parvalbumin-containing interneurons of the human cerebral cortex express nicotinic acetylcholine receptor proteins.

Cholinergic fibers from the basal forebrain are known to contact cholinoceptive cortical pyramidal neurons. Recent electrophysiological studies have revealed that nicotinic acetylcholine receptors are also present in human cerebrocortical interneurons. A direct visualization of nicotinic receptor subunits in cortical interneurons has, however, not yet been performed. We have applied double-immunofluorescence using antibodies against parvalbumin --a marker for the Chandelier and basket cell subpopulation of interneurons--and to the alpha4 and alpha7 subunit proteins of the nicotinic acetylcholine receptor. The vast majority of the parvalbuminergic interneurons was immunoreactive for the alpha4 and the alpha7 nicotinic acetylcholine receptor. Provided these receptors would be functional--as suggested by recent electrophysiological findings--the connectivity pattern of cholinergic afferents appears much more complex than thought before. Not only direct cholinergic impact on cortical projection neurons but also the indirect modulation of these by cholinergic corticopetal fibers contacting intrinsic cortical cells would be possible.

Adult↗
PubMed2000

Classical Alzheimer features and cholinergic dysfunction: towards a unifying hypothesis?

OBJECTIVE: Our autopsy studies show possible links between classical Alzheimer pathology and decreased expression of nicotinic acetylcholine receptors. For further elucidation we are now using in vitro models. We report preliminary evidence for the impact of beta-amyloid on nicotinic receptor expression in hippocampal dissociation culture. METHODS: Cultures (E18 rats) were grown in a serum-free medium and incubated at 8 days in vitro for 3 days with 1 microM Abeta1-42. Expression of alpha4, alpha7, and beta2 nicotinic receptor subunit protein was assessed immunohistochemically and rated semiquantitatively. RESULTS: Abeta1-42 incubation resulted in a massive reduction of alpha4 protein-expressing neurons, this effect was less pronounced for the alpha7 and beta2 subunit protein. CONCLUSION: These findings provide first evidence for a direct impact of classical Alzheimer pathology features on nicotinic receptor expression in vitro. Our model will be useful for testing the potential of drugs to stop or reverse these effects.

Alzheimer Disease↗
PubMed2000

Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer's disease, Parkinson's disease, and experimental hypertension. What is the functional link?

The brain, as an intensely active organ, is highly dependent on a sufficient nutrient and oxygen availability in order to reach its optimal working capacity. It is well known that the vital supply of energy substrates is provided by the circulatory system, which splits up into a fine, terminal capillary network in target tissues. These capillaries are considered as important sites, since the actual nutrient trafficking takes place through their walls. That is why an intact, preserved structure of the microvessels is crucial to fulfill their function. Since the brain is known to be particularly vulnerable to suboptimal oxygen and glucose delivery, the intact morphology of capillaries is of paramount importance. Several observations have indicated that the cerebral capillary ultrastructure is damaged in Alzheimer's disease (AD). Curiously, the regional cerebral blood flow of AD patients is also significantly lower than in age-matched control individuals. Based on these data, it has been suggested that the decreased blood supply and the cerebrovascular alterations contribute to the development of dementia. However, we have observed similar capillary damage in Parkinson's disease patients and chronically hypertensive rats in addition to AD cases, as presented here. These findings indicate that cerebral capillary damage is not exclusive for AD but occurs under other neurodegenerative disorders and hypertension, as well. We hypothesize that ultrastructural abnormalities of cerebral capillaries are causally related to decreased cerebral blood flow and create a condition that favors neurodegenerative mechanisms including the development of dementia.

Alzheimer Disease↗
PubMed1999

Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease.

Potential genomic changes leading to decreased nicotine binding, crucial for cognitive dysfunction in Alzheimer's disease (AD), have not yet been studied. A search for mutations of the genes coding for the most widely distributed nicotinic receptor subtype alpha4beta2 (CHRNA4/CHRNB2) has been performed in AD patients by screening the coding regions of both genes by single strand conformation analysis and heteroduplex analysis of fibroblast-derived genomic DNA. Polymorphisms in CHRNA4, none of which led to amino acid changes in the predicted sequence, were found in three patients. Although the other receptor subunits have yet to be screened, it appears likely that the reduction of nicotine binding sites in AD is not due to genomic changes.

Aged↗
PubMed1999

Decreased concentration of annexin V in parkinsonian cerebrospinal fluid: speculation on the underlying cause.

Circumstantial evidence suggests that increased apoptosis is responsible for the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD). It is impossible to perform high-quality studies on human postmortem material because of the low quality of tissue preservation, and the fact that apoptosis has a duration of only hours, and that the duration of the agonal period itself will lead to massive neuronal cell death. We measured, as epiphenomenon of neuronal cell death ex vivo, the Annexin V concentration in cerebrospinal fluid (CSF) in patients with PD and control subjects. The Annexin V concentration in CSF of patients with PD was significantly lower compared with control subjects. Annexin V concentrations of the CSF did not correlate with dementia, duration of symptoms, age, sex, or treatment of PD. The rationale for measurement of Annexin V in CSF is the fact that Annexin V adheres to dying cells. It is tempting to suppose that the decrease of Annexin V in CSF of PD is the result of consumption of this protein during neuronal apoptosis as has been demonstrated to occur in the midbrain in PD.

Adult↗
PubMed1999

Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein.

Impairment of cholinergic transmission and decreased numbers of nicotinic binding sites are well-known features accompanying the cognitive dysfunction seen in Alzheimer's disease (AD). In order to elucidate the underlying cause of this cholinoceptive dysfunction, the expression of two pharmacologically different nicotinic acetylcholine receptor (nAChR) subunits (alpha4, alpha7) was studied in the cerebral cortex of Alzheimer patients as compared to controls. Patch-clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of alpha4- and alpha7-containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of alpha4 and alpha7 mRNA-expressing neurons were similar, whereas at the protein level a decrease in the density of alpha4- and alpha7-expressing neurons of approximately 30% was observed in Alzheimer patients. The histotopographical correlation of nAChR expression with accompanying pathological changes, e.g. accumulation of hyperphosphorylated-tau (HP-tau) protein and beta-amyloid showed that neurons in the vicinity of beta-amyloid plaques bore both nAChR transcripts. Neurons heavily labelled for HP-tau, however, expressed little or no alpha4 and alpha7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholinoceptive deficit in AD. Further investigations need to elucidate whether interactions of HP-tau with nAChR mRNA, or alterations in the quality of alpha4 and alpha7 transcripts give rise to decreased protein expression at the level of individual neurons.

Aged↗
PubMed1997

Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies.

Although cognitive impairment during aging is usually associated with neuronal alterations, the cerebrovascular system undergoes prominent alterations in aging as well. Using electron microscopy we previously showed a progressive deterioration of the capillary wall in the cerebral cortex of aged rats. In aged rats the capillary basement membrane (BM) is thickened, massive bundles of collagen fibrils are deposited within the BM, and pericytes are degenerating. A compromized cerebral circulation (e.g., in rats with chronic hypertension) is characterized by an increased number of capillary alterations. In autopsy material (gray matter, gyrus cinguli) of carefully diagnosed patient groups (controls, AD, Lewy body disease, MID and demented Lewy body disease patients) we observed significantly more morphological changes in the capillary bed of demented versus non-demented patients. In both animal and human material morphological evidence points to a relation between energy-dependent nutrient transport across the blood-brain barrier and the ultrastructural deviations. In the AD cases we did not find a correlation between the stage of the disease (Braak I-VI) and the incidence of capillary aberrations, which indicates that the capillary alterations are not a consequence of AD pathology. Simultaneously, we are conducting animal model studies to determine the effects of cerebral hypoperfusion in the rat. Permanent bilateral occlusion of the carotid arteries shifts the behavioral profile of the rats (Morris maze, open field) towards that of aged rats, while the sensitivity for muscarinic ligand agents is altered.

Aging↗
PubMed1997

Apolipoprotein E genotyping in patients with neurodegenerative diseases.

OBJECTIVES: There is a growing demand to perform apolipoprotein E (Apo-E) genotyping on neuropathologic archive material. Due to the extremely long fixation time, this material is unsuitable for routinely used Apo-E genotyping methods. We present an investigation into the applicability of a new method. DESIGN AND METHODS: An Apo-E genotyping method was tested for use on formalin-fixed paraffin-embedded brain tissue, using semi-nested PCR followed by hybridization with biotin-labeled allele-specific oligonucleotides, and chemiluminescent detection. The method was applied to 88 archive samples of different neurologic disorders. RESULTS: With this technique 76% (67/88) of the samples could be genotyped. The crucial step is the semi-nested PCR. All the samples from which a PCR product could be obtained, the Apo-E gene could be genotyped without interpretation problems. Seventy-six percent of the samples that could not be genotyped, were fixed in unbuffered formalin. CONCLUSIONS: This technique offers a good Apo-E genotyping method applicable on neuropathological archive material in order to support in retrospect clinical studies.

Alzheimer Disease↗
PubMed1993

Increase of Parkinson disability after fluoxetine medication.

Depression is a major clinical feature of Parkinson's disease. We report the increased amount of motor disability in four patients with idiopathic Parkinson's disease after exposure to the antidepressant fluoxetine. The possibility of a clinically relevant dopamine-antagonistic capacity of fluoxetine in Parkinson's disease patients must be considered.

Fluoxetine↗