Search PubMed⌕ Search

Biomedical subjects

Thomas Arendt

Publications and source records attributed to Thomas Arendt.

At least 55 records · Page 3Linked to original sources
PubMed2004

Detection of nitric oxide synthase (NOS) immunoreactive neurons in the human septal area: a matter of method?

There is a remarkable discrepancy between biochemical and cell morphological findings with regard to the presence of NADPH diaphorase/neuronal nitric oxide synthase (NOS) in the primate septal area. Whereas considerable concentrations of neuronal nitric oxide synthase and high enzyme activities have been measured in postmortem human septal nuclei, histochemical studies were either unable to detect any nitric oxide synthase immunoreactivity in primate septal neurons, or found only a very few nitrergic neurons in this region. This study aimed to investigate the possible presence of nitrergic neurons in human the septal region in greater detail. After having studied a total of 16 postmortem human brains we conclude that the immunohistochemical demonstration of nitric oxide synthase in human septal neurons is largely dependent on the mode of tissue handling: in brain specimens which were fixed en-bloc with paraffin and embedded in paraplast, nitric oxide synthase immunoreactivity is barely detectable, whereas a satisfying immunostaining is obtained on free-floating frozen sections after an immersion-fixation with 4% paraformaldehyde and 0.5% glutaraldehyde, followed by sucrose protection of the specimens. We show herein that there are indeed nitric oxide synthase-containing neurons in the human septum, thus supporting results from previous biochemical studies.

Artifacts↗
PubMed2004

Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex.

In Alzheimer's disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In this study, we show that neuronal immunoreactivity for phosphorylated p38 MAPK does not correlate with COX-2 or phosphorylated pRb (ppRb) in control and AD temporal cortex. Immunoreactivity for activated p38 MAPK co-localizes with AT8 immunoreactivity and increases with the occurrence of neurofibrillary tangles and plaques. On the other hand, COX-2 immunoreactivity co-localizes and correlates with ppRb immunoreactivity in pyramidal neurons. COX-2 and ppRb do not co-localize with AT8 and decrease with increasing pathology. These results suggest that p38 MAPK does not mediate COX-2 expression and pRb inactivation, which are involved in cellular changes in pyramidal neurons early in AD pathogenesis.

Aged↗
PubMed2004

Structural correlates of mild cognitive impairment.

The structural correlates of mild cognitive impairment (MCI) were examined in 105 elderly subjects whose cognitive function ranged from intact to demented, including 38 subjects with MCI. Hippocampal volumes (left and right HcV), brain volume (BV), and grey matter volume (GMV) and white matter volume (WMV) were segmented from high resolution magnetic resonance data sets and normalised to intracranial volume (ICV). Hippocampal volume reductions, but not global brain, white or grey matter atrophy, were associated with MCI. White matter lesion severity did not differ over cognitive states. In multiple logistic regression models, normalised HcV and ICV (indicating premorbid brain volume) were significant predictors of MCI versus normality. Normalised BV and ICV significantly predicted dementia versus MCI. Absolute volumetric measures of HcV and BV yielded comparable classification accuracies. Hippocampal atrophy may be the crucial step for the transition from normality to MCI. Widespread brain atrophy may be the step to determine the transition from MCI to dementia. Brain volume reserve effects appear to be involved in both of these steps.

Aged↗
PubMed2004

Regional patterns of gene expression in human and chimpanzee brains.

We have analyzed gene expression in various brain regions of humans and chimpanzees. Within both human and chimpanzee individuals, the transcriptomes of the cerebral cortex are very similar to each other and differ more between individuals than among regions within an individual. In contrast, the transcriptomes of the cerebral cortex, the caudate nucleus, and the cerebellum differ substantially from each other. Between humans and chimpanzees, 10% of genes differ in their expression in at least one region of the brain. The majority of these expression differences are shared among all brain regions. Whereas genes encoding proteins involved in signal transduction and cell differentiation differ significantly between brain regions within individuals, no such pattern is seen between the species. However, a subset of genes that show expression differences between humans and chimpanzees are distributed nonrandomly across the genome. Furthermore, genes that show an elevated expression level in humans are statistically significantly enriched in regions that are recently duplicated in humans.

Adult↗
PubMed2004

Neuronal activation of Ras regulates synaptic connectivity.

A synRas mouse model was used expressing constitutively activated Ha-Ras (Val12 mutation) in neurons to investigate the role of Ras-MAPkinase signalling for neuronal connectivity in adult brain. Expression of the transgene in the cortex of these mice starts after neuronal differentiation is completed and allows to directly investigate the effects of enhanced Ras activity in differentiated neurons. Activation of Ha-Ras induced an increase in soma size which was sensitive to MEK inhibitor in postnatal organotypic cultures. Adult cortical pyramidal neurons showed complex structural rearrangements associated with an increased size and ramification of dendritic arborization. Dendritic spine density was elevated and correlated with a twofold increase in number of synapses. In acute brain slices of the somatosensory and of the visual cortex, extracellular field potentials were recorded from layer II/III neurons. The input-output relation of synaptically evoked field potentials revealed a significantly higher basal excitability of the transgenic mice cortex compared to wild-type animals. In whole cell patch clamp preparations, the frequency of AMPA receptor-mediated spontaneous excitatory postsynaptic currents was increased while the ratio between NMDA and AMPA-receptor mediated signal amplitude was unchanged. A pronounced depression of paired pulse facilitation indicated that Ras contributes to changes at the presynaptic site. Furthermore, synRas mice showed an increased synaptic long-term potentiation, which was sensitive to blockers of NMDA-receptors and of MEK. We conclude that neuronal Ras is a common switch of plasticity in adult mammalian brain sculpturing neuronal architecture and synaptic connectivity in concert with tuning synaptic efficacy.

2-Amino-5-phosphonovalerate↗
PubMed2003

Constitutive expression of p21H-Ras(Val12) in neurons induces increased axonal size and dendritic microtubule density in vivo.

The small G protein p21Ras is a key signal transducer mediating cellular growth and proliferation responses to extracellular stimuli. We investigated by electron microscopy the effects of augmented p21Ras activity on neuronal processes and microtubule arrangement in vivo. We used transgenic mice with a neuron-specific overexpression of p21H-RasVal12, which starts postnatally around Day 15. Axonal and dendritic diameters and the numerical density of dendritic microtubules were analyzed at postnatal Day 12 before the onset of transgene expression and in adult mice. In adult transgenic mice, calibers of both axons (corpus callosum) and dendrites (layers II/III of somatosensory cortex) were enlarged by about 57% and 79%, respectively. The increase in dendritic calibers was associated with an increment in the amount of microtubules. Even in dendrites of equivalent diameters, the number of microtubules was higher in transgenic mice compared to that in wild-type mice suggesting an elevated microtubule density. Changes in process diameters or microtubule density were not observed at postnatal Day 12 before relevant transcription of transgenic p21H-RasVal12. The present results extend previous findings on neuronal hypertrophy as a consequence of p21H-RasVal12 expression and suggest a profound influence on the dendritic microtubule network.

Animals↗
PubMed2003

Expression of constitutively active p21H-rasval12 in postmitotic pyramidal neurons results in increased dendritic size and complexity.

The small G protein p21Ras is a critical molecular switch for relaying neurotrophic actions and is essential for normal functioning and plasticity of the nervous system. In this study, the morphogenetic effects of p21Ras were investigated on neurons in vivo. Morphological changes of layers II/III and Vb commissural pyramidal neurons of the primary somatosensory cortex were analyzed in transgenic mice expressing permanently active p21H-RasVal12 in postmitotic neurons. Pyramidal cells were retrogradely labelled with biotinylated dextran amine and subsequently traced using Neurolucida. Compared with wild-type mice, transgenic animals showed a significant increase in the surface area and volume of basal dendrites on the proximal and intermediate segments in layers II/III and on further distal segments in layer V. In addition, the surface area and volume of the trunk and of the proximal segments of oblique branches of apical dendrites were enlarged in both layers. Sholl analyses of basal and apical dendrites showed a significant increase in dendritic complexity of layer V neurons. A positive correlation was observed between the size of the basal dendrite and the neuronal soma size in the transgenic population, indicating that growth-promoting effects of p21H-RasVal12 affect both cellular compartments in parallel. However, the dendritic surface correlated with the number of tips and dendritic stem diameter in both wild-type and transgenic populations, demonstrating that these relations represent rather conservative design principles in dendritic morphology. The data presented here suggest an important role of p21Ras-dependent signaling in the final differentiation and maintenance of dendritic morphology.

Animals↗
PubMed2003

Complementary distribution of vesicular glutamate transporters 1 and 2 in the nucleus accumbens of rat: Relationship to calretinin-containing extrinsic innervation and calbindin-immunoreactive neurons.

The caudomedial shell of the rat nucleus accumbens exhibits inhomogeneous distribution patterns of the vesicular glutamate transporters 1 (VGLUT1) and 2 (VGLUT2). This paper focuses on the question of whether patterns of VGLUT1 and VGLUT2 correspond to cytoarchitectonically and cytochemically defined subterritories of the caudomedial shell region. VGLUT2 was shown to be coexpressed with calretinin in the dense axonal plexus known to emanate from the paraventricular thalamic nucleus. In regions termed corridors, which are spared by this paraventricular thalamic innervation, axonal terminals were found to be clustered and VGLUT1-immunoreactive. It is assumed that these fibers originate in the prelimbic cortex and/or in the parvicellular basal amygdaloid nucleus known to project to accumbal shell components. Our findings confirm the existence of two well-separated neuronal circuits in the caudomedial shell that are dominated by two different excitatory input systems originating from either thalamic, cortical, or cortex-like amygdaloid sources. The large lateral corridors-which resemble the accumbal core not only in respect to their VGLUT1 immunolabeling but also concerning their content of calbindin-positive cells-may represent a component of the anatomically weakly defined accumbal shore region.

Afferent Pathways↗
PubMed2003

Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the intracellular accumulation of highly phosphorylated tau protein, the extracellular formation of amyloid plaques and a significant loss of neurons. Recent evidence suggests that neuronal death in AD involves an aborted attempt of cells to re-enter the cell cycle. To study the effect of amyloid deposits on cell cycle related events in vivo, the expression of cell cycle markers was examined by immunohistochemistry in amyloid precursor protein (APP) transgenic mice (APP23 mice, Swedish double mutation). Abeta deposition in APP23 mice is associated with prominent gliosis that is characterized by an astrocytic expression of cyclins D1, E and B1 as well as the nuclear translocation of cyclin-dependent protein kinase 4. However, amyloid plaque formation is not accompanied by significant changes in the neuronal expression of cyclins or cyclin-dependent kinase inhibitors. It is concluded, therefore, that in contrast to AD, amyloid pathology in APP23 mice is not associated with changes in the expression of cell cycle markers in neurons. The results support the assumption that the neuronal re-expression of cell cycle components in AD is not a consequence of Abeta formation and deposition.

Alzheimer Disease↗
PubMed2003

Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals.

Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.

Adaptation, Physiological↗
PubMed2003

Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice.

Cholinergic dysfunction is a consistent feature of Alzheimer's disease, and the interrelationship between beta-amyloid deposits, inflammation and early cholinergic cell loss is still not fully understood. To characterize the mechanisms by which beta-amyloid and pro-inflammatory cytokines may exert specific degenerating actions on cholinergic cells ultrastructural investigations by electron microscopy were performed in brain sections from transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein and progressively develop beta-amyloid plaques during aging. Both light and electron microscopical investigations of the cerebral cortex of 19-month-old transgenic mice revealed a number of pathological tissue responses in close proximity of beta-amyloid plaques, such as activated microglia, astroglial proliferation, increased number of fibrous astrocytes, brain edema, degeneration of nerve cells, dendrites and axon terminals. Ultrastructural detection of choline acetyl transferase (ChAT)-immunostaining in cerebral cortical sections of transgenic mice clearly demonstrated degeneration of ChAT-immunoreactive fibres in the environment of beta-amyloid plaques and activated glial cells suggesting a role of beta-amyloid and/or inflammation in specific degeneration of cholinergic synaptic structures.

Alzheimer Disease↗
PubMed2003

Reelin-immunoreactive Cajal-Retzius cells: the entorhinal cortex in normal aging and Alzheimer's disease.

Alzheimer's disease (AD) is a disorder of brain self organization associated with morphodysregulation at the synaptic level. Disturbances follow a hierarchical spatio-temporal pattern throughout the cortex and involve the re-activation of developmental molecular programs. The large glycoprotein reelin, synthesized by Cajal-Retzius (CR) cells, is an important component of a signaling pathway involved in embryonic development and modulation of synaptic circuitry, but is also implicated in the pathogenetic cascade in AD. Although the majority of CR cells sequentially disappears from the postnatal cortical layer I, a few of them persist in the normal adult brain. They continue to produce reelin, express a variety of other proteins, and are characterized by a typical morphology. Recently, CR cells have been reported to be altered in number and morphology in a variety of neurological and psychiatric diseases linked to maldevelopment. In the present study we show that reelin-positive CR cells persist in the layer I of the entorhinal cortex in normal senescent brains and are also preserved in AD. The majority of CR cells in AD is morphologically and cytochemically-as revealed by double labeling with calcium-binding proteins-indistinguishable from normal cases, suggesting that they are not dramatically altered in the entorhinal cortex of AD patients. Nevertheless, CR cells seem to be partially affected by the formation of paired helical filaments, indicating subtle changes that are suggested to be a result rather than a cause of the pathogenetic cascade of AD.

Aged↗
PubMed2003

The relationship between head size and intracranial volume in elderly subjects.

OBJECTIVE: To study the relationship between parenchymal head volume (PHV) and intracranial volume (ICV), and to compare the ability of these two measurements to reflect the association between maximum mature brain volume and late-life cognition. METHODS: An elderly sample of humans with a range of cognitive functions from normality, via mild cognitive impairment (MCI) to dementia (mean age 78.6, S.D. 2.8; mean MMSE 25.4, S.D. 4.2) was examined. Head-to-head measurements of ICV and parenchymal head volume (PHV) were obtained from three-dimensional T1 weighted magnetic resonance images using automated procedures. Analyses of cognitive functions were based on continuous and categorial variables. RESULTS: PHV explained 55% of the variance in ICV. The ratio between PHV and ICV remained constant with increasing age and cognitive impairment. Measurements of PHV and ICV yielded comparable correlations with global cognitive performance. Group differences over gender and cognitive states were equally present in ICV and PHV. The relative risks of cognitive impairment that were associated with either small ICV or PHV were comparable. CONCLUSIONS: Measures of PHV can be considered as useful estimates of ICV and cerebral volume reserve.

Aged↗
PubMed2003

Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity.

Mental actions are based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits) involved in the realization of higher brain functions are continuously re-adjusted to meet environmental demands. The mechanisms of synaptic plasticity, i.e., of structural stabilization and labilization underlying a life-long synaptic remodelling, are largely based on external morphoregulatory cues and internal signalling pathways that non-neuronal cells have phylogenetically acquired to sense their relationship to the local neighbourhood and to control after development is completed proliferation and differentiation in the process of tissue repair and regeneration. After having withdrawn from the cell cycle, differentiated neurons are, thus, able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it at risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

Alzheimer Disease↗
PubMed2002

Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation.

Various isoforms of the nitric oxide (NO) producing enzyme nitric oxide synthase (NOS) are elevated in Alzheimer's disease (AD) indicating a critical role for NO in the pathomechanism. NO can react with superoxide to generate peroxynitrite, a process referred to as oxidative stress, which is likely to play a role in AD. Peroxynitrite in turn, nitrates tyrosine residues to form nitrotyrosine which can be identified immunohistochemically. To study the potential structural link between the increased synthesis of NO and the deposition of nitrotyrosine in AD, we analyzed the expression of neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) in AD and control brain, and compared the localization with the distribution of nitrotyrosine. Nitrotyrosine was detected in neurons, astrocytes and blood vessels in AD cases. Aberrant expression of nNOS in cortical pyramidal cells was highly co-localized with nitrotyrosine. Furthermore, iNOS and eNOS were highly expressed in astrocytes in AD. In addition, double immunolabeling studies revealed that in these glial cells iNOS and eNOS are co-localized with nitrotyrosine. Therefore, it is suggested that increased expression of all NOS isoforms in astrocytes and neurons contributes to the synthesis of peroxynitrite which leads to generation of nitrotyrosine. In view of the wide range of isoform-specific NOS inhibitors, the determination of the most responsible isoform of NOS for the formation of peroxynitrite in AD could be of therapeutic importance in the treatment of Alzheimer's disease.

Aged↗
PubMed2002

Inverse association of Pin1 and tau accumulation in Alzheimer's disease hippocampus.

Neurofibrillary degeneration, one of the pathological hallmarks of Alzheimer's disease, is not ubiquitous to all brain regions or neurons. While a high degree of vulnerability has been documented for entorhinal cortex, hippocampal and neocortical pyramidal neurons other brain structures are largely spared. Even within highly vulnerable regions such as hippocampus neurons are affected to a variable extent. The molecular basis for this selective susceptibility remains unknown. Neurofibrillary degeneration involves hyperphosphorylation of tau which critically impairs its binding capacity to microtubule and, therefore, is believed to disrupt the axonal cytoskeleton. Recently, Lu et al. [Nature (1999) 399:784] described the ability of the peptidyl-prolyl cis-trans isomerase Pin1 to recover microtubule-binding affinity and microtubule stabilisation of phosphorylated tau. In the present study, we analysed the potential involvement of Pin1 in selective vulnerability of hippocampal neurons to neurofibrillary degeneration in Alzheimer's disease. Pin1 immunoreactivity appeared as cytoplasmic granules affecting hippocampal subfields to a different extent (CA2>subiculum>CA1>CA3/CA4). Since the main markers of granulovacuolar degeneration do not co-label Pin1-immunoreactive granules, we propose that these granules may represent a new lesion in Alzheimer's disease. Neurons containing Pin1 granules were devoid of neurofibrillary tangles. Granular accumulation of Pin1 may correspond to an absence of neurofibrillary lesions in these cells and might be associated with other mechanisms of neuronal degeneration.

Aged↗
PubMed2002

Intraneuronal advanced glycation endproducts in presenilin-1 Alzheimer's disease.

The most frequently mutated gene resulting in dominantly inherited Alzheimer's disease is presenilin-1. We have used antibodies against advanced glycation endproducts (AGE) in brain tissue sections of four patients with three different presenilin I mutations. Accumulation of intracellular AGE was observed in 75-95% of pyramidal neurons in patients with presenilin-1 mutations, far exceeding the percentage of presenilin-1-, tau- or ubiquitin-positive neurons. This high level of AGE-modified proteins in vulnerable neurons is most likely explained by higher levels of their precursors (reactive (di)carbonyl products) or a slower turnover of the participating proteins. These conditions of carbonyl stress may contribute to increased neuronal dysfunction and vulnerability leading to the early disease onset.

Adult↗