Publisher Summary Neurotrophic factors such as nerve growth factor (NGF) influence the survival a... more Publisher Summary Neurotrophic factors such as nerve growth factor (NGF) influence the survival and/or differentiation of multiple neuronal populations. In particular, the neurotrophins, including NGF and brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5, are abundantly expressed in the central nervous system. One neuronal population in the brain that has been extensively studied for neurotrophin responsiveness is the basal forebrain (BF) cholinergic system, which is particularly vulnerable to degeneration in Alzheimer's disease. This population expresses TrkA, TrkB, and TrkC, the high-affinity receptors for NGF, BDNF, NT-4/5, and NT-3, respectively, and the low-affinity neurotrophin receptor, p75. This chapter discusses the influence of neurotrophins on the survival of BF cholinergic neurons, cholinergic cells, and distinction in the regulation of cholinergic neuron survival versus regulation of choline acetyltransferase (ChAT) enzyme activity. Low doses of NGF and BDNF act synergistically to facilitate the survival of basal forebrain cholinergic and GABAergic neurons. As both NGF and BDNF are present in the target hippocampus, the interactive effects of these factors may critically influence the BF in vivo. Moreover, the trophic effects on neuronal survival may be distinguished from those on phenotypic expression of ChAT activity by dose dependence.
The precise timing of neural progenitor development and the correct balance between proliferation... more The precise timing of neural progenitor development and the correct balance between proliferation and differentiation are crucial to generating a functional brain. The number, survival, and differentiation of neural progenitors during postnatal neurogenesis and gliogenesis is a highly regulated process. Postnatally, the majority of brain oligodendrocytes are generated from progenitors residing in the subventricular zone (SVZ), the germinal niche surrounding the lateral ventricles. In this study, we demonstrate that the p75 neurotrophin receptor (p75NTR) is highly expressed by OPCs in the postnatal male and female rat SVZ. Whereas the p75NTR is known to initiate apoptotic signaling after brain injury, it is highly expressed by proliferating progenitors in the SVZ, suggesting that it may have a different function during development. Lack of p75NTR reduced progenitor proliferation and caused premature oligodendrocyte differentiation and maturation both in vitro and in vivo, leading to ...
IntroductionRecently, the cerebellum has been implicated with non-motor functions, including cogn... more IntroductionRecently, the cerebellum has been implicated with non-motor functions, including cognitive and emotional behavior. Anatomical and functional studies demonstrate bidirectional cerebellar connections with brain regions involved in social cognition. Cerebellar developmental abnormalities and injury are often associated with several psychiatric and mental disorders including autism spectrum disorders and anxiety. The cerebellar granule neurons (CGN) are essential for cerebellar function since they provide sensorimotor, proprioceptive, and contextual information to Purkinje cells to modify behavior in different contexts. Therefore, alterations to the CGN population are likely to compromise cerebellar processing and function. Previously we demonstrated that the p75 neurotrophin receptor (p75NTR) was fundamental for the development of the CGN. In the absence of p75NTR, we observed increased proliferation of the granule cell precursors (GCPs), followed by increased GCP migration...
SummaryNeuronal migration is one of the fundamental processes during brain development. Several n... more SummaryNeuronal migration is one of the fundamental processes during brain development. Several neurodevelopmental disorders can be traced back to dysregulated migration. Although substantial efforts have been placed in identifying molecular signals that stimulate migration, little is known about potential mechanisms that restrict migration. These restrictive mechanisms are essential for proper development since it helps coordinate the timing for each neuronal population to arrive and establish proper connections. Moreover, preventing migration away from a proliferative niche is necessary to maintain a pool of proliferating cells until the proper number of neuronal progenitors is attained.Here, we identify an anti-migratory role for the p75 neurotrophin receptor (p75NTR) in cerebellar development. Our results show that granule cell precursors robustly express p75NTR in the external granule layer (EGL) when they are proliferating during postnatal development, however, they do not exp...
In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxida... more In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.
Publisher Summary Neurotrophic factors such as nerve growth factor (NGF) influence the survival a... more Publisher Summary Neurotrophic factors such as nerve growth factor (NGF) influence the survival and/or differentiation of multiple neuronal populations. In particular, the neurotrophins, including NGF and brain-derived neurotrophic factor (BDNF), NT-3, and NT-4/5, are abundantly expressed in the central nervous system. One neuronal population in the brain that has been extensively studied for neurotrophin responsiveness is the basal forebrain (BF) cholinergic system, which is particularly vulnerable to degeneration in Alzheimer's disease. This population expresses TrkA, TrkB, and TrkC, the high-affinity receptors for NGF, BDNF, NT-4/5, and NT-3, respectively, and the low-affinity neurotrophin receptor, p75. This chapter discusses the influence of neurotrophins on the survival of BF cholinergic neurons, cholinergic cells, and distinction in the regulation of cholinergic neuron survival versus regulation of choline acetyltransferase (ChAT) enzyme activity. Low doses of NGF and BDNF act synergistically to facilitate the survival of basal forebrain cholinergic and GABAergic neurons. As both NGF and BDNF are present in the target hippocampus, the interactive effects of these factors may critically influence the BF in vivo. Moreover, the trophic effects on neuronal survival may be distinguished from those on phenotypic expression of ChAT activity by dose dependence.
The precise timing of neural progenitor development and the correct balance between proliferation... more The precise timing of neural progenitor development and the correct balance between proliferation and differentiation are crucial to generating a functional brain. The number, survival, and differentiation of neural progenitors during postnatal neurogenesis and gliogenesis is a highly regulated process. Postnatally, the majority of brain oligodendrocytes are generated from progenitors residing in the subventricular zone (SVZ), the germinal niche surrounding the lateral ventricles. In this study, we demonstrate that the p75 neurotrophin receptor (p75NTR) is highly expressed by OPCs in the postnatal male and female rat SVZ. Whereas the p75NTR is known to initiate apoptotic signaling after brain injury, it is highly expressed by proliferating progenitors in the SVZ, suggesting that it may have a different function during development. Lack of p75NTR reduced progenitor proliferation and caused premature oligodendrocyte differentiation and maturation both in vitro and in vivo, leading to ...
IntroductionRecently, the cerebellum has been implicated with non-motor functions, including cogn... more IntroductionRecently, the cerebellum has been implicated with non-motor functions, including cognitive and emotional behavior. Anatomical and functional studies demonstrate bidirectional cerebellar connections with brain regions involved in social cognition. Cerebellar developmental abnormalities and injury are often associated with several psychiatric and mental disorders including autism spectrum disorders and anxiety. The cerebellar granule neurons (CGN) are essential for cerebellar function since they provide sensorimotor, proprioceptive, and contextual information to Purkinje cells to modify behavior in different contexts. Therefore, alterations to the CGN population are likely to compromise cerebellar processing and function. Previously we demonstrated that the p75 neurotrophin receptor (p75NTR) was fundamental for the development of the CGN. In the absence of p75NTR, we observed increased proliferation of the granule cell precursors (GCPs), followed by increased GCP migration...
SummaryNeuronal migration is one of the fundamental processes during brain development. Several n... more SummaryNeuronal migration is one of the fundamental processes during brain development. Several neurodevelopmental disorders can be traced back to dysregulated migration. Although substantial efforts have been placed in identifying molecular signals that stimulate migration, little is known about potential mechanisms that restrict migration. These restrictive mechanisms are essential for proper development since it helps coordinate the timing for each neuronal population to arrive and establish proper connections. Moreover, preventing migration away from a proliferative niche is necessary to maintain a pool of proliferating cells until the proper number of neuronal progenitors is attained.Here, we identify an anti-migratory role for the p75 neurotrophin receptor (p75NTR) in cerebellar development. Our results show that granule cell precursors robustly express p75NTR in the external granule layer (EGL) when they are proliferating during postnatal development, however, they do not exp...
In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxida... more In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.
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