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M K Brückner

Publications and source records attributed to M K Brückner.

At least 19 recordsLinked to original sources
PubMed2003

Analyzing the neocortical fine-structure.

Cytoarchitectonic fields of the human neocortex are defined by characteristic variations in the composition of a general six-layer structure. It is commonly accepted that these fields correspond to functionally homogeneous entities. Diligent techniques were developed to characterize cytoarchitectonic fields by staining sections of post-mortem brains and subsequent statistical evaluation. Fields were found to show a considerable interindividual variability in extent and relation to macroscopic anatomical landmarks. With upcoming new high-resolution magnetic resonance imaging (MRI) protocols, it appears worthwhile to examine the feasibility of characterizing the neocortical fine-structure from anatomical MRI scans, thus, defining neocortical fields by in vivo techniques. A fixated brain hemisphere was scanned at a resolution of approximately 0.3 mm. After correcting for intensity inhomogeneities in the dataset, the cortex boundaries (the white/grey matter and grey matter/background interfaces) were determined as a triangular mesh. Radial intensity profiles following the shortest path through the cortex were computed and characterized by a sparse set of features. A statistical similarity measure between features of different regions was defined, and served to define the extent of Brodmann's Areas 4, 17, 44 and 45 in this dataset.

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

Developmentally induced microencephalopathy in guinea pigs--embryonic glial cell activation marks selective neuronal death.

We have recently shown that in utero treatment of guinea pigs with the DNA methylating substance methylazoxymethanol acetate (MAM) on gestation day (GD) 24 results in neocortical microencephalopathy, increased protein kinase C activity and altered processing of the amyloid precursor protein in neocortex of the offsprings. In order to identify the primary neuronal lesions produced by MAM-treatment, we mapped the 5-bromo-2'-deoxyuridine (BrdU)-incorporation in dividing neurons on GD 24 and we followed the effects of MAM-treatment on GD 24 on embryonic immediate early gene expression and on glial cell activation. BrdU injected on GD 24 labeled many neurons of the ventricular zone and of the intermediate zone but only scattered neurons of the cortical plate. When time-mated guinea pigs were injected intraperitoneally with MAM on GD 24, we observed the activation of microglial cells in the ventricular/intermediate zone and the appearence of astrocytes between the intermediate zone and the cortical plate, 48 h after intoxification. The activation of glial cells was accompanied by the neuronal expression of c-Fos but not of c-Jun in the ventricular/intermediate zone. Based on our observations on BrdU-incorporation and on the morphological outcome of MAM treatment in the juvenile guinea pig, our data presented here indicate that selective neurodegeneration during development induces the activation of both phagocytotic microglial cells and of astrocytes which might trophically support damaged neurons surviving this lesion procedure.

Amyloid beta-Protein Precursor↗
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↗
PubMed2000

Guinea-pig primary cell cultures provide a model to study expression and amyloidogenic processing of endogenous amyloid precursor protein.

Until now guinea-pigs have been rarely used to investigate formation and deposition of Alzheimer's disease-associated amyloid beta peptides despite the sequence identity of human and guinea-pig amyloid beta peptides being known, and the overall similarity of human and guinea-pig amyloid precursor protein. We now describe a primary cell culture system of mixed fetal guinea-pig brain cells, which we have applied to characterize endogenous amyloid precursor protein processing and amyloid beta formation. These cell cultures were established at embryonic day 24 of guinea-pigs after comparison of selected stages of guinea-pig ontogenetic development with the known ontogeny of rats, and were characterized by immunocytochemical detection of neuronal and glial marker proteins. Amyloid precursor protein expression, processing and amyloid beta formation increased in parallel with cellular maturation during cultivation and reached a stable phase after approximately 14 days in vitro therefore providing a suitable time for analysis. Aged cultures display strong neuronal amyloid precursor protein immunoreactivity and an altered profile of amyloid precursor protein isoform messenger RNA expression due to glial proliferation as single neurons were shown to retain their typical pattern of amyloid precursor protein expression. We show that amyloid precursor protein in guinea-pig cells is processed by different protease activities which most likely represent alpha- and beta-secretase, leading to the generation of soluble amyloid precursor protein derivatives. Furthermore, endogenous amyloid precursor protein processing leads to production of substantial amounts of amyloid beta-peptides which accumulate in conditioned culture medium. Amyloid beta was readily detectable by western blot analysis and was shown to consist of approximately 80-90% amyloid beta(1-40). We suggest that primary guinea-pig cell cultures provide a valuable tool in amyloid research that resembles amyloid precursor protein processing under physiological concentrations and, therefore, the situation in humans more closely than current rodent models. It should be especially useful in screening experiments for secretase inhibiting compounds.

Amyloid↗
PubMed2000

Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death.

Neurodegeneration in Alzheimer's disease (AD) is associated with the appearance of dystrophic neuronal growth profiles that most likely reflect an impairment of neuronal reorganization. This process of morphodysregulation, which eventually goes awry and becomes a disease itself, might be triggered either by a variety of life events that place an additional burden on the plastic capability of the brain or by genetic pertubations that shift the threshold for decompensation. This paper summarizes recent evidence that impairment of the p21ras intracellular signal transduction, which is is mediated by a hierarchy of phosphorylation signals and eventually results in loss of differentiation control and an attempt of neurons to re-enter the cell-cycle, is critically involved in this process. Neurodegeneration might thus be viewed as an alternative effector pathway of those events that in the dividing cell would lead to cellular transformation. This hypothesis might be of heuristic value for the development of a therapeutic strategy.

Alzheimer Disease↗
PubMed1999

Activities of key glycolytic enzymes in the brains of patients with Alzheimer's disease.

The activities of hexokinase, aldolase, pyruvate kinase, lactate dehydrogenase and glucose 6-phosphate dehydrogenase were determined in brains of patients with Alzheimer's disease (AD) and in age matched controls. For pyruvate kinase and lactate dehydrogenase a significant increase in specific activity was found in frontal and temporal cortex of AD brains, while the activities of aldolase and hexokinase are not changed. Glucose 6-phosphate dehydrogenase activity was significantly reduced in hippocampus. The increase of some glycolytic enzyme activities is correlated with increased contents of lactate dehydrogenase and glial fibrillary acidic protein (GFAP) in homogenates of frontal and temporal cortex and elevated phosphofructokinase (PFK) and GFAP in astrocytes from the same brain areas. The data extend previous findings on an increase in brain PFK specific activity in AD and suggest that the increased activity of some glycolytic enzymes may be, at least in part, the result of the reactive astrocytosis developing in the course of AD.

Aged↗
PubMed1999

Cortical load of PHF-tau in Alzheimer's disease is correlated to cholinergic dysfunction.

To assess a potential relationship between cortical neurofibrillary degeneration and cortical cholinergic deafferentation, the load of PHF-tau was analysed in eight cortical regions and in the basal nucleus of Meynert in 12 cases with Alzheimer's disease by means of a sensitive ELISA employing the monoclonal antibody B5-2. The activity of choline acetyltransferase was determined on identical tissue samples. The results demonstrate a highly correlative relationship between the cortical distribution of the amount of PHF-tau, mainly present in neuropil threads, and cholinergic depletion early during the course of the disease. This relationship was less strong in more advanced stages. The results support the suggestion that the formation of PHF-tau in cholinergic axon terminals which might result in a loss of cholinergic synapses and a cholinergic dysconnection of the cortex, is an early event in AD. During the progression of the disease, formation of PHF-tau appears to spread over the cortex which results in a more even distribution of neuropil threads and a progressive involvement of non-cholinergic neurons.

Aged↗
PubMed1998

Aberrancies in signal transduction and cell cycle related events in Alzheimer's disease.

Neurodegeneration in Alzheimer's disease (AD) is associated with the appearance of dystrophic neuronal growth profiles that most likely reflects an aberrant attempt of neuronal repair. This process of neuronal reorganisation, which eventually goes awry and becomes a disease itself, might be initiated physiologically as a response to neuronal injuries. Minor neuronal damage due to a variety of life events or genetic pertubations that are usually compensated in the normal adult brain by adaptation and repair might thus be amplified and accumulated, thereby resulting in a progressive neurodegeneration. The present paper summarizes recent evidence supporting the hypothesis that a primary impairment of intracellular signal transduction that is mediated by a hierarchy of phosphorylation signals and associated with a aborted attempt of neurons to re-enter the cell-cycle is a key element in the pathomechanism of AD. These changes might result in malfunction of neuronal adaptation and repair and eventually lead to neuronal death. During the process of aging as well as in chronic neurodegenerative disorders such as Alzheimer's disease (AD), the continuous but rather slow action of pathogenetic factors might give room for the activation of compensatory mechanisms, serving to regain a neuronal population much of its synaptic connectivity in the presence of cell loss. An upregulation in the capacity to synthesize and store neurotransmitters (Lapchak et al., 1991), an increased expression of trophic factors (Hellweg et al., 1990; Arendt et al., 1995a,b), as well as regenerative sprouting (Fritschy and Grzanna, 1992), synaptic enlargement (Scheff et al., 1990; Lippa et al., 1992), and neosynaptogenesis (Ramirez and Ulfhake, 1992) have been described among other processes.

Adult↗
PubMed1998

Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain.

The formation of neurofibrillary tangles in Alzheimer's disease shows a preferential involvement of certain cytoarchitecturally defined cortical areas suggesting systematic differences in regional neuronal vulnerability. The cellular and molecular nature of this selective neuronal vulnerability that follows a certain hierarchy of structural brain organization is largely unknown. In the present study, we compared the regional pattern of tangle density in Alzheimer's disease with systematic regional differences in neuronal plasticity that can be observed both during ageing and in Alzheimer's disease. Changes in dendritic length and arborization of Golgi-impregnated pyramidal neurons were analysed after three-dimensional reconstruction in 12 cortical areas. The intensity of dendritic remodelling that was observed during ageing as well as in Alzheimer's disease was regionally different and decreased in the following order: transentorhinal region > limbic areas (entorhinal region, hippocampus) > non-primary association areas (37, 40, 46) > primary sensory association areas (7, 18, 22) > primary sensory and motor cortex (17, 41, 4). These regional differences of neuronal plasticity follow the same pattern as the regional vulnerability to tangle formation in Alzheimer's disease. The results of the present study provide evidence that a high degree of structural neuronal plasticity might predispose neurons to tangle formation.

Adult↗
PubMed1997

Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele.

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system. In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE epsilon 4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE epsilon 4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE epsilon 4 allele was very weak in the presence of one epsilon 4 allele and completely lost in patients homozygous for the epsilon 4 allele. The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE epsilon 4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

Aged↗
PubMed1997

Differential changes in the expression of AMPA receptors genes in rat brain after chronic exposure to ethanol: an in situ hybridization study.

Chronic treatment with ethanol of adult rat was used as an experimental paradigm to investigate changes in the expression of glutamate receptor genes under the condition of a slowly progressing neurodegeneration that is associated with a plastic neuronal growth response. Effects of chronic oral ethanol exposure (20% v/v, 28 weeks) on the expression of the AMPA receptor mRNA subtypes GluR-A, GluR-B and GluR-C (flip variants) were analysed in the rat hippocampus by in situ hybridization and subsequent quantitative autoradiography. In both controls and ethanol treated animals strong hybridization signals could be detected over pyramidal neurones and dentate gyrus cells. GluR-C mRNA was elevated by 15% to 30%, while expression of the AMPA receptor transcripts GluR-A and GluR-B were not significantly altered after ethanol treatment. The present findings demonstrate that chronic ethanol exposure affects gene expression of AMPA receptor subtypes differentially. Differential influences of distinct AMPA-receptor subtypes on neuronal survival and plastic neuronal response under conditions of chronic neuronal degeneration might, therefore, be suggested.

Alcoholism↗
PubMed1996

NGF level in the rat sciatic nerve is decreased after long-term consumption of ethanol.

Long-term effects of ethanol consumption on endogenous nerve growth factor (NGF) level were investigated in NGF-producing target organs and tissues of the peripheral nervous system. Rats were treated with ethanol (20% v/v) for 9 months, detoxified for an additional 2 weeks and kept without ethanol for an additional month prior to sacrifice. NGF level in the NGF-producing target tissues such as iris and submandibular gland and in the trigeminal ganglion and superior cervical ganglion, where NGF-responsive perikarya are located, did not differ significantly from corresponding controls. In contrast, NGF level in the sciatic nerve was significantly reduced by 54%. This indicates that long-term ethanol consumption affects retrograde axonal transport of the neurotrophic factor NGF, suggesting that NGF deficiency may be part of the pathophysiology of peripheral neuropathy due to chronic alcoholism.

Alcoholism↗
PubMed1995

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. I. Dendritic organisation of the normal human basal forebrain.

In the present study, the dendritic organisation of neurones in the normal human basal forebrain was analysed as a prerequisite for the evaluation of pathological changes occurring in Alzheimer's disease and related conditions (see other Arendt et al. papers in this issue). Neurones in the basal nucleus of Meynert (NbM), the nucleus of the vertical limb of the diagonal band, and the medial septal nucleus were examined after Golgi impregnation. Cells were classified according to the dendritic branching pattern and soma shape as either reticular neurones or multipolar giant neurones. The reticular type of neurones constitutes more than 90% of neurones in the BnM. Cholinergic neurones also belong to this cell type. Reticular neurones were further subdivided into four subtypes. Morphological features and arrangement of reticular basal forebrain neurones were identical to those described for "reticular formation cells" or "isodendritic" neurones. Dendritic trees of reticular neurones show a spatial orientation perpendicular to passing fibres as well as a high degree of overlap, both of which are hallmarks of "open nuclei." The qualitative classification of Golgi-impregnated basal forebrain neurones was substantiated by a computer-based three-dimensional analysis. Topologic and metric parameters of the dendritic tree were calculated for each type of neurone to characterise the degree of dendritic branching, the shape and orientation of the dendritic arborisation, the spatial extension of the dendritic tree, and soma size. The classification criteria were evaluated according to their power of discrimination between different cell types by means of a discriminant analysis. The quantitative approach applied in the present study not only provides an objective measure for the description and comparison of the structure of various types of neurones but also makes it possible to elucidate fine structural changes that might occur under pathologic conditions and that are not evident during qualitative studies alone.

Adult↗
PubMed1995

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. II. Ageing, Korsakoff's disease, Parkinson's disease, and Alzheimer's disease.

Changes in the dendritic arborisation of Golgi-impregnated basal forebrain neurones with respect to size, shape, orientation, and topology of branching were quantitatively investigated in ageing, Alzheimer's disease (AD), Korsakoff's disease (KD), and Parkinson's disease (PD). A reorganisation of the whole dendritic tree characterized by an increase in both the total dendritic length and the degree of dendritic arborisation as well as by changes in the shape of the dendritic field was found during ageing, in KD, PD, and AD. Dendritic growth under these conditions was related to the extent of cell loss in basal forebrain nuclei. There appeared to be major differences, however, with respect to the overall pattern of dendritic reorganisation between AD on one side and ageing, KD, and PD on the other side. In both ageing and KD, dendritic growth was largely restricted to the terminal dendritic segments, resulting in an increase of the size of the dendritic field (pattern of "extensive growth") In AD, however, dendritic growth mainly resulted in an increase of the dendritic density within the dendritic field without being accompanied by an increase in the size of the volume occupied by the dendritic tree (pattern of "intensive growth"). In AD, aberrant growth processes were frequently observed in the perisomatic area or on distal dendritic segments of basal forebrain neurones of the reticular type. Neurones with aberrant growth profiles were typically located in the direct vicinity of deposits of beta/A4 amyloid. Perisomatic growth profiles were covered by the low-affinity receptor of nerve growth factor p75NGFR. Aberrant growth processes were not present in ageing, KD, and PD. On the basis of the present study, it is concluded that under certain degenerative conditions, reticular basal forebrain neurones undergo a compensatory reorganisation of their dendritic arborisation, a process that has become defective in AD, thereby converting a physiological signal into a cascade of events contributing to the pathology of the disease.

Adult↗
PubMed1995

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. III. The basal forebrain compared with other subcortical areas.

The distribution of the reticular neuronal type in the human brain and its involvement in both degeneration and dendritic reorganisation under the conditions of ageing, Korsakoff's disease (KD), Alzheimer's disease (AD), and Parkinson's disease (PD) was comparatively investigated after Golgi impregnation. Reticular neurones are distributed throughout different areas along the brain axis. The cholinergic basal forebrain nuclei, i.e., the basal nucleus of Meynert, the nucleus of the diagonal band, and the medial septal nucleus form the most rostral part of this network of "open nuclei," which is collectively referred to as the "reticular core." Reticular neurones of the following areas were quantitatively investigated by a computer-based three-dimensional analysis: caudate nucleus, globus pallidus, medial septal nucleus, nucleus of the vertical limb of the diagonal band, basal nucleus, medial amygdaloid nucleus, reticular thalamic nucleus, lateral hypothalamic area, subthalamic nucleus, substantia nigra, locus coeruleus, pedunculopontine tegmental nucleus, and raphe magnus nucleus. There are three major findings. First, neurones that were found to be susceptible to degeneration in AD were largely part of the same neuronal populations prone to degeneration during ageing, in KD and PD. Thus, areas could be classified according to their overall degree of vulnerability under the present degenerative conditions as being highly vulnerable (basal forebrain nuclei, caudate nucleus, locus coeruleus), moderately vulnerable (medial amygdaloid nucleus, raphe magnus nucleus, lateral hypothalamic area, substantia nigra, pedunculopontine tegmental nucleus), or marginally vulnerable (globus pallidus, subthalamic nucleus, reticular thalamic nucleus). Second, neuronal populations that are particularly vulnerable to degenerative changes show a high degree of structural plasticity. Third, the degree of this dendritic plasticity is inversely related to the complexity of dendritic arborisation of the neurone. It is concluded that the sparsely ramified reticular type of neurone forms a pool of pluripotent neurones that have retained their plastic capacity throughout life, which makes them vulnerable to a variety of perturbations.

Adult↗
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↗