Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2018
The reasons for the high number of loosened metal‐on‐metal (MoM) hip implants are still not fully... more The reasons for the high number of loosened metal‐on‐metal (MoM) hip implants are still not fully understood. Hypoxia‐inducible factor 1 (HIF‐1) mediated signaling pathways, which normally modulate tissue metabolism under hypoxic circumstances, could be triggered by metallic wear debris and influence bone metabolism favoring osteolysis. This may lead to early loosening of the orthopedic implants. Immunhistochemical staining of periprosthetic tissues of failed artificial hip implants showed that the concentration of HIF‐1α in the surrounding tissues of failed MoM hip implants was significantly higher in comparison to failed metal‐on‐polyethylene (MoP) hip implants and osteoarthritic tissues. Therefore, we examined the Co2+‐uptake mechanisms and the influence of Co2+ uptake on HIF‐1α stabilization. Based on cobalt mediated quenching effects, calcium imaging experiments using fura‐2 showed a concentration‐dependent cobalt influx in MG‐63 cells, which could be inhibited by the unspecifi...
1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derive... more 1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and Neurotrophin-3, -4/5, and -6 (NT-3; NT-4/5; NT-6) is well known to enhance the survival and to stabilize the phenotype of different populations of neurons in the central and the peripheral nervous system. These effects are mediated via binding to specific tyrosine kinase receptors (Trks) and to the low-affinity p75 neurotrophin receptor. 2. The neurotrophins NGF, BDNF, and NT-3 and the BDNF and NT-3 selective receptors (TrkB, TrkC) are expressed at high levels in neurons of the basal forebrain, the hippocampus, and the neocortex of the mammalian brain. The expression and secretion of NGF and BDNF in these brain areas is regulated by (physiological levels of) neuronal activity. 3. Exogenous application of the neurotrophins to hippocampal and neocortical neurons can enhance excitatory glutamatergic synaptic transmission via activation of Trk receptors. In addition, long-term potentiation (a potential cellular correlate for learning and memory formation in mammals) in the rodent hippocampus depends on endogenous supply of neurons with BDNF. 4. Judged by the analysis of electrophysiological data, the BDNF- and NT-3-induced enhancement of glutamatergic synapses is mediated by increasing the efficacy of glutamate release from the presynaptic neuron. However, neurotrophin-dependent postsynaptic enhancement of NMDA (but not AMPA) receptor responsiveness has also been shown. 5. On the molecular level, neither the pre- nor the postsynaptic modulation of glutamatergic synapses by neurotrophins is well understood. However, neurotrophins were shown to acutely affect intraneuronal Ca2+ levels and to influence molecular components of the transmitter release machinery, which could underly the presynaptic modifications, whereas BDNF-induced phosphorylation of NMDA-type glutamate receptors could account for the postsynaptic effects. 6. Taken together, these results suggest that the activity-dependent release of neurotrophins at frequently used synapses could modulate the synaptic efficacy at these junctions. Thus, neurotrophins might operate as locally released feedback modulators of synaptic transmission, and this could be a cellular correlate for certain aspects of information processing in the mammalian brain.
doi: 10.3389/fnbeh.2015.00058 Impact of an additional chronic BDNF reduction on learning performa... more doi: 10.3389/fnbeh.2015.00058 Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model
Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well kn... more Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF knock-out mice (BDNF+/−). Since brain BDNF levels are known to decline with aging, we hypothesized that BDNF+/− mice might show reduced fear learning at older ages. Indeed, BDNF+/− animals revealed an age-dependent deficit in fear learning 3 mo after birth and beyond. Since there were no alterations between the two genotypes during the conditioning training and when testing short-term memory, this learning deficit most likely reflects a deficit in memory consolidation. Importantly, there were no differences in spontaneous motor behavior and baseline anxiety in BDNF+/− animals at any age tested. Following behavioral testing quantification of BDNF...
An essential part of the excitatory afferent input to the thalamus is mediated by glutamate recep... more An essential part of the excitatory afferent input to the thalamus is mediated by glutamate receptors of the AMPA/kainate type. In contrast to other regions of the mammalian CNS, the biophysical properties of these receptors have not been investigated in thalamic neurones. Using a fast transmitter application system we studied L-glutamate activated currents of cultured neurones in the whole cell and outside-out patch configuration. Current-voltage relationships and dose-response curves of whole cell recordings were in close correspondence to results obtained from other brain areas. Analysis of outside-out patch currents revealed two types of desensitization time constants of 3.0 and 10.2 ms, with the former close to the time constant of decay of miniature glutamatergic synaptic currents.
The protein family of mammalian neurotrophins, comprising nerve-growth factor (NGF), brain-derive... more The protein family of mammalian neurotrophins, comprising nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 and -4/5 (NT-3, NT-4/5), supports the survival and the phenotype of neurons from the central as well as the peripheral nervous system (CNS, PNS). In addition, exogenous application of neurotrophins has recently been found to modulate synaptic transmission in the rodent CNS. However, to provide evidence for a role of neurotophins as endogenous fast acting modulators of synaptic transmission, the synaptic localization and secretion of neurotrophins needs to be shown. We have now constructed a fusion protein consisting of N-terminal BDNF (the most abundant neurotrophin in the rodent hippocampus and neocortex) and C-terminal green fluorescent protein (GFP) to elucidate the cellular localization of BDNF in cortical neurons. Transient expression of BDNF-GFP in COS-7 cells revealed that the cellular localization in the trans-Golgi network (TGN), the ...
Incubation of the human monoblastoid tumor cell line U937 with 5 x 10(-9) M 12-O-tetradecanoylpho... more Incubation of the human monoblastoid tumor cell line U937 with 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days was associated with marked morphological and functional changes including adherence of the cells and cessation of proliferation. While growth arrest and the viability of the cells were not influenced, the TPA-induced adherence of U937 cells could be totally blocked by incubation with tunicamycin, suggesting an involvement of N-linked carbohydrates in these cell attachment processes. The isolation and characterization of endogenous lectins with specificities for lactose, L-fucose, and D-mannose from U937 controls and TPA-differentiated U937 cells demonstrated marked differences in either the pattern and the distribution of these sugar-specific carbohydrate-binding proteins. Our results indicate that alterations in cell-surface carbohydrates are of central importance for the attachment of the differentiating U937 tumor cells.
Memories are believed to be represented by facilitated synaptic transmission of electrical signa... more Memories are believed to be represented by facilitated synaptic transmission of electrical signals in neuronal networks. The ability to acquire new memories or to change old memory content results from the plastic properties of the brain. Molecular changes in synaptic plasticity of neuronal networks are considered to be the cellular correlates of learning and memory, and the neurotrophin brain-derived neurotropic factor (BDNF) plays an important role in these processes. This neurotrophic factor coordinates a multitude of biological functions. In addition to its role in neuronal plasticity processes, such as long-term potentiation of synaptic transmission, the protein regulates the differentiation of neuronal precursor cells, synaptogenesis, and neuronal survival. Cellular processes like BDNF protein processing, anterograde and retrograde transport, as well as exocytosis and endocytosis of BDNF vesicles are necessary to enable the protein to fulfill its neuroprotective and...
Memories are believed to be represented by facilitated synaptic transmission of electrical signal... more Memories are believed to be represented by facilitated synaptic transmission of electrical signals in neuronal networks. The ability to acquire new memories or to change old memory content results from the plastic properties of the brain. Molecular changes in synaptic plasticity of neuronal networks are considered to be the cellular correlates of learning and memory, and the neurotrophin brain-derived neurotropic factor (BDNF) plays an important role in these processes. This neurotrophic factor coordinates a multitude of biological functions. In addition to its role in neuronal plasticity processes, such as long-term potentiation of synaptic transmission, the protein regulates the differentiation of neuronal precursor cells, synaptogenesis, and neuronal survival. Cellular processes like BDNF protein processing, anterograde and retrograde transport, as well as exocytosis and endocytosis of BDNF vesicles are necessary to enable the protein to fulfill its neuroprotective and plasticity...
Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2018
The reasons for the high number of loosened metal‐on‐metal (MoM) hip implants are still not fully... more The reasons for the high number of loosened metal‐on‐metal (MoM) hip implants are still not fully understood. Hypoxia‐inducible factor 1 (HIF‐1) mediated signaling pathways, which normally modulate tissue metabolism under hypoxic circumstances, could be triggered by metallic wear debris and influence bone metabolism favoring osteolysis. This may lead to early loosening of the orthopedic implants. Immunhistochemical staining of periprosthetic tissues of failed artificial hip implants showed that the concentration of HIF‐1α in the surrounding tissues of failed MoM hip implants was significantly higher in comparison to failed metal‐on‐polyethylene (MoP) hip implants and osteoarthritic tissues. Therefore, we examined the Co2+‐uptake mechanisms and the influence of Co2+ uptake on HIF‐1α stabilization. Based on cobalt mediated quenching effects, calcium imaging experiments using fura‐2 showed a concentration‐dependent cobalt influx in MG‐63 cells, which could be inhibited by the unspecifi...
1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derive... more 1. The protein family of the neurotrophins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and Neurotrophin-3, -4/5, and -6 (NT-3; NT-4/5; NT-6) is well known to enhance the survival and to stabilize the phenotype of different populations of neurons in the central and the peripheral nervous system. These effects are mediated via binding to specific tyrosine kinase receptors (Trks) and to the low-affinity p75 neurotrophin receptor. 2. The neurotrophins NGF, BDNF, and NT-3 and the BDNF and NT-3 selective receptors (TrkB, TrkC) are expressed at high levels in neurons of the basal forebrain, the hippocampus, and the neocortex of the mammalian brain. The expression and secretion of NGF and BDNF in these brain areas is regulated by (physiological levels of) neuronal activity. 3. Exogenous application of the neurotrophins to hippocampal and neocortical neurons can enhance excitatory glutamatergic synaptic transmission via activation of Trk receptors. In addition, long-term potentiation (a potential cellular correlate for learning and memory formation in mammals) in the rodent hippocampus depends on endogenous supply of neurons with BDNF. 4. Judged by the analysis of electrophysiological data, the BDNF- and NT-3-induced enhancement of glutamatergic synapses is mediated by increasing the efficacy of glutamate release from the presynaptic neuron. However, neurotrophin-dependent postsynaptic enhancement of NMDA (but not AMPA) receptor responsiveness has also been shown. 5. On the molecular level, neither the pre- nor the postsynaptic modulation of glutamatergic synapses by neurotrophins is well understood. However, neurotrophins were shown to acutely affect intraneuronal Ca2+ levels and to influence molecular components of the transmitter release machinery, which could underly the presynaptic modifications, whereas BDNF-induced phosphorylation of NMDA-type glutamate receptors could account for the postsynaptic effects. 6. Taken together, these results suggest that the activity-dependent release of neurotrophins at frequently used synapses could modulate the synaptic efficacy at these junctions. Thus, neurotrophins might operate as locally released feedback modulators of synaptic transmission, and this could be a cellular correlate for certain aspects of information processing in the mammalian brain.
doi: 10.3389/fnbeh.2015.00058 Impact of an additional chronic BDNF reduction on learning performa... more doi: 10.3389/fnbeh.2015.00058 Impact of an additional chronic BDNF reduction on learning performance in an Alzheimer mouse model
Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well kn... more Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF knock-out mice (BDNF+/−). Since brain BDNF levels are known to decline with aging, we hypothesized that BDNF+/− mice might show reduced fear learning at older ages. Indeed, BDNF+/− animals revealed an age-dependent deficit in fear learning 3 mo after birth and beyond. Since there were no alterations between the two genotypes during the conditioning training and when testing short-term memory, this learning deficit most likely reflects a deficit in memory consolidation. Importantly, there were no differences in spontaneous motor behavior and baseline anxiety in BDNF+/− animals at any age tested. Following behavioral testing quantification of BDNF...
An essential part of the excitatory afferent input to the thalamus is mediated by glutamate recep... more An essential part of the excitatory afferent input to the thalamus is mediated by glutamate receptors of the AMPA/kainate type. In contrast to other regions of the mammalian CNS, the biophysical properties of these receptors have not been investigated in thalamic neurones. Using a fast transmitter application system we studied L-glutamate activated currents of cultured neurones in the whole cell and outside-out patch configuration. Current-voltage relationships and dose-response curves of whole cell recordings were in close correspondence to results obtained from other brain areas. Analysis of outside-out patch currents revealed two types of desensitization time constants of 3.0 and 10.2 ms, with the former close to the time constant of decay of miniature glutamatergic synaptic currents.
The protein family of mammalian neurotrophins, comprising nerve-growth factor (NGF), brain-derive... more The protein family of mammalian neurotrophins, comprising nerve-growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 and -4/5 (NT-3, NT-4/5), supports the survival and the phenotype of neurons from the central as well as the peripheral nervous system (CNS, PNS). In addition, exogenous application of neurotrophins has recently been found to modulate synaptic transmission in the rodent CNS. However, to provide evidence for a role of neurotophins as endogenous fast acting modulators of synaptic transmission, the synaptic localization and secretion of neurotrophins needs to be shown. We have now constructed a fusion protein consisting of N-terminal BDNF (the most abundant neurotrophin in the rodent hippocampus and neocortex) and C-terminal green fluorescent protein (GFP) to elucidate the cellular localization of BDNF in cortical neurons. Transient expression of BDNF-GFP in COS-7 cells revealed that the cellular localization in the trans-Golgi network (TGN), the ...
Incubation of the human monoblastoid tumor cell line U937 with 5 x 10(-9) M 12-O-tetradecanoylpho... more Incubation of the human monoblastoid tumor cell line U937 with 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days was associated with marked morphological and functional changes including adherence of the cells and cessation of proliferation. While growth arrest and the viability of the cells were not influenced, the TPA-induced adherence of U937 cells could be totally blocked by incubation with tunicamycin, suggesting an involvement of N-linked carbohydrates in these cell attachment processes. The isolation and characterization of endogenous lectins with specificities for lactose, L-fucose, and D-mannose from U937 controls and TPA-differentiated U937 cells demonstrated marked differences in either the pattern and the distribution of these sugar-specific carbohydrate-binding proteins. Our results indicate that alterations in cell-surface carbohydrates are of central importance for the attachment of the differentiating U937 tumor cells.
Memories are believed to be represented by facilitated synaptic transmission of electrical signa... more Memories are believed to be represented by facilitated synaptic transmission of electrical signals in neuronal networks. The ability to acquire new memories or to change old memory content results from the plastic properties of the brain. Molecular changes in synaptic plasticity of neuronal networks are considered to be the cellular correlates of learning and memory, and the neurotrophin brain-derived neurotropic factor (BDNF) plays an important role in these processes. This neurotrophic factor coordinates a multitude of biological functions. In addition to its role in neuronal plasticity processes, such as long-term potentiation of synaptic transmission, the protein regulates the differentiation of neuronal precursor cells, synaptogenesis, and neuronal survival. Cellular processes like BDNF protein processing, anterograde and retrograde transport, as well as exocytosis and endocytosis of BDNF vesicles are necessary to enable the protein to fulfill its neuroprotective and...
Memories are believed to be represented by facilitated synaptic transmission of electrical signal... more Memories are believed to be represented by facilitated synaptic transmission of electrical signals in neuronal networks. The ability to acquire new memories or to change old memory content results from the plastic properties of the brain. Molecular changes in synaptic plasticity of neuronal networks are considered to be the cellular correlates of learning and memory, and the neurotrophin brain-derived neurotropic factor (BDNF) plays an important role in these processes. This neurotrophic factor coordinates a multitude of biological functions. In addition to its role in neuronal plasticity processes, such as long-term potentiation of synaptic transmission, the protein regulates the differentiation of neuronal precursor cells, synaptogenesis, and neuronal survival. Cellular processes like BDNF protein processing, anterograde and retrograde transport, as well as exocytosis and endocytosis of BDNF vesicles are necessary to enable the protein to fulfill its neuroprotective and plasticity...
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Papers by V. Lessmann