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Induction of glial glutaminyl cyclase expression in rodent brain under pathological conditions
Poster Abstracts / Int. J. Devl Neuroscience 28 (2010) 655–719
[P1.65] Altered habituation and synaptic properties in Drosophila AKAP (rugose) mutants A. Wise 1,∗ , X. Zhong 2 , A. Ueda 2 , C.F. Wu 2 , T. Venkatesh 1 , et al 1
City College of New York, USA University of Iowa, USA Keywords: A kinase anchoring proteins; Habituation; Rugose; Neuromuscular junction 2
Habituation is a form of non-associative conditioning in which there is a reduction in response to a specific stimulus presented repetitively over time. Components of the cAMP mediated signaling pathway have been previously shown to be important for normal habituation. A kinase anchoring proteins (AKAPS) are a large family of proteins originally identified in mammals which modulate the specificity of protein kinase A (PKA) function by targeting and compartmentalizing PKA to various sub-cellular structures. Rugose (rg) encodes a Drosophila A kinase anchor protein (DAKAP550) which has been previously shown to be required normal pattern formation in the developing eye (Shamloula et al 2002). We present data which show mutations in rugose(rg), which encodes a (DAKAP550) alter habituation and synaptic properties. Data from behavioral, electrophysiological and cell biological studies on the adult as well as the larval neuromuscular junction are presented here. doi:10.1016/j.ijdevneu.2010.07.105 [P1.66] Shh pathway impairment in neuronal precursor cells from the subventricular zone of the Ts65Dn mouse, an animal model for Down Syndrome V.M. Mitrugno ∗ , S. Trazzi, R. Bartesaghi, E. Ciani University of Bologna, Italy Keywords: Ts65Dn mouse; Neurospheres; Sonic Hedgehog (Shh) pathway; Down Syndrome Mental retardation in Down Syndrome (trisomy 21) appears to be related to severe neurogenesis impairment during critical phases of brain development. It has been recently shown that the reduced proliferation of cerebellar granule cell precursors from Ts65Dn mice is related to an attenuated response to sonic hedgehog (Shh), a potent mitogen that controls cell division during brain development. The goal of current study was (i) to establish whether also neuronal precursor cells from the subventricular zone of Ts65Dn mice exhibit defective response to Shh and (ii) to dissect the molecular mechanism/s underlying deregulation of the Shh pathway. We found that cultured neuronal precursor cells (neurospheres) from neonate Ts65Dn mice had a reduced proliferation rate compared to controls, similarly to the in vivo condition. Unlike in euploid neurospheres, in Ts65Dn neurospheres the Shh mitogenic stimulus was unable to increase proliferation. In Ts65Dn neurospheres, the expression levels of the Shh receptor Patched1 (Ptch) were increased compared to controls both at the RNA and protein level. In the absence of Shh, Ptch interacts with smoothened (Smo), thereby suppressing the Shh signal transduction pathway and this repression is released when Ptch binds Shh. We found that in Ts65Dn neurospheres various target genes of the pathway, including Gli1 and N-Myc, were down regulated. In agreement with impairment of the Shh pathway, Shh administration failed to increase the expression of these genes. By contrast, treatment with SAG1, an agonist that directly binds to Smo, promoted cell proliferation and increased Gli1 expression, suggesting that impairment
677
of the Shh pathway is due to a Ptch-dependent inhibition. Results suggest that derangement of the Shh pathway may be a generalized defect in neuronal precursors of the trisomic brain and show, for the first time, that derangement of this pathway is most likely due to overexpression of Ptch. doi:10.1016/j.ijdevneu.2010.07.106 [P1.67] Induction of glial glutaminyl cyclase expression in rodent brain under pathological conditions S. Rossner ∗ , M. Hartlage-Rübsamen, J. Brune University of Leipzig, Germany Keywords: Alzheimer’s disease; Gliosis; Abeta; Glutaminyl cyclase Brains from Alzheimer’s disease (AD) patients are characterized by the degeneration of defined neuronal populations, neurofibrillary tangles and deposits of Abeta peptides. A substantial proportion of deposited Abeta peptides is N-terminally truncated and carries a pyroglutamate modification. This modification is catalyzed by glutaminyl cyclase (QC) and confers high aggregation velocity, neurotoxicity and resistance to proteolysis. Therefore, QC attains much attention as a novel pharmacological target for AD therapy. Recent immunohistochemical studies demonstrated a primarily neuronal QC expression in normal rodent brain. However, epidemiological studies revealed an association of brain traumata accompanied by glial cell activation with AD pathogenesis. We therefore asked whether QC expression is induced in glial cells under pathological conditions and analyzed cell type specific QC expression in brains of (i) normal mice, (ii) amyloid precursor protein transgenic tg2576 mice and (iii) rats after immunotoxic lesions of defined neuronal populations. In the unmanipulated brain QC was exclusively expressed by neurons and localized to the endoplasmatic reticulum, Golgi apparatus and secretory granules, consistent with a QC function in neuronal protein maturation and/or modification. However, in different neuronal lesion paradigms QC was also found to be induced in glial cells. So we observed astroglial QC expression associated with Abeta plaques in tg2576 mice. Moreover, following immunotoxic lesions of cholinergic and dopaminergic neurons in rat brain we detected astrocytic and microglial QC expression. Glial QC immunoreactivity was also observed in primary cultrures from mouse brain. Our results indicate that distinct kinds of lesions induce a differential glial response which involves QC expression and might, therefore, contribute to amyloidogenesis and inflammation. doi:10.1016/j.ijdevneu.2010.07.107 [P1.68] Ephrin-B1 reverse signaling controls a post-transcriptional feedback mechanism in neural progenitors D.N. Arvanitis 1,2 , T. Jungas 1,2 , A. Behar 1,2 , A. Davy 1,2,∗ 1
CNRS, France Universite de Toulouse, France Keywords: Ephrins; miRNAs; Cortical development; Neural progenitors 2
Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known on the mechanisms regulating their expression. Here we report that the expression
[P1.65] Altered habituation and synaptic properties in Drosophila AKAP (rugose) mutants A. Wise 1,∗ , X. Zhong 2 , A. Ueda 2 , C.F. Wu 2 , T. Venkatesh 1 , et al 1
City College of New York, USA University of Iowa, USA Keywords: A kinase anchoring proteins; Habituation; Rugose; Neuromuscular junction 2
Habituation is a form of non-associative conditioning in which there is a reduction in response to a specific stimulus presented repetitively over time. Components of the cAMP mediated signaling pathway have been previously shown to be important for normal habituation. A kinase anchoring proteins (AKAPS) are a large family of proteins originally identified in mammals which modulate the specificity of protein kinase A (PKA) function by targeting and compartmentalizing PKA to various sub-cellular structures. Rugose (rg) encodes a Drosophila A kinase anchor protein (DAKAP550) which has been previously shown to be required normal pattern formation in the developing eye (Shamloula et al 2002). We present data which show mutations in rugose(rg), which encodes a (DAKAP550) alter habituation and synaptic properties. Data from behavioral, electrophysiological and cell biological studies on the adult as well as the larval neuromuscular junction are presented here. doi:10.1016/j.ijdevneu.2010.07.105 [P1.66] Shh pathway impairment in neuronal precursor cells from the subventricular zone of the Ts65Dn mouse, an animal model for Down Syndrome V.M. Mitrugno ∗ , S. Trazzi, R. Bartesaghi, E. Ciani University of Bologna, Italy Keywords: Ts65Dn mouse; Neurospheres; Sonic Hedgehog (Shh) pathway; Down Syndrome Mental retardation in Down Syndrome (trisomy 21) appears to be related to severe neurogenesis impairment during critical phases of brain development. It has been recently shown that the reduced proliferation of cerebellar granule cell precursors from Ts65Dn mice is related to an attenuated response to sonic hedgehog (Shh), a potent mitogen that controls cell division during brain development. The goal of current study was (i) to establish whether also neuronal precursor cells from the subventricular zone of Ts65Dn mice exhibit defective response to Shh and (ii) to dissect the molecular mechanism/s underlying deregulation of the Shh pathway. We found that cultured neuronal precursor cells (neurospheres) from neonate Ts65Dn mice had a reduced proliferation rate compared to controls, similarly to the in vivo condition. Unlike in euploid neurospheres, in Ts65Dn neurospheres the Shh mitogenic stimulus was unable to increase proliferation. In Ts65Dn neurospheres, the expression levels of the Shh receptor Patched1 (Ptch) were increased compared to controls both at the RNA and protein level. In the absence of Shh, Ptch interacts with smoothened (Smo), thereby suppressing the Shh signal transduction pathway and this repression is released when Ptch binds Shh. We found that in Ts65Dn neurospheres various target genes of the pathway, including Gli1 and N-Myc, were down regulated. In agreement with impairment of the Shh pathway, Shh administration failed to increase the expression of these genes. By contrast, treatment with SAG1, an agonist that directly binds to Smo, promoted cell proliferation and increased Gli1 expression, suggesting that impairment
677
of the Shh pathway is due to a Ptch-dependent inhibition. Results suggest that derangement of the Shh pathway may be a generalized defect in neuronal precursors of the trisomic brain and show, for the first time, that derangement of this pathway is most likely due to overexpression of Ptch. doi:10.1016/j.ijdevneu.2010.07.106 [P1.67] Induction of glial glutaminyl cyclase expression in rodent brain under pathological conditions S. Rossner ∗ , M. Hartlage-Rübsamen, J. Brune University of Leipzig, Germany Keywords: Alzheimer’s disease; Gliosis; Abeta; Glutaminyl cyclase Brains from Alzheimer’s disease (AD) patients are characterized by the degeneration of defined neuronal populations, neurofibrillary tangles and deposits of Abeta peptides. A substantial proportion of deposited Abeta peptides is N-terminally truncated and carries a pyroglutamate modification. This modification is catalyzed by glutaminyl cyclase (QC) and confers high aggregation velocity, neurotoxicity and resistance to proteolysis. Therefore, QC attains much attention as a novel pharmacological target for AD therapy. Recent immunohistochemical studies demonstrated a primarily neuronal QC expression in normal rodent brain. However, epidemiological studies revealed an association of brain traumata accompanied by glial cell activation with AD pathogenesis. We therefore asked whether QC expression is induced in glial cells under pathological conditions and analyzed cell type specific QC expression in brains of (i) normal mice, (ii) amyloid precursor protein transgenic tg2576 mice and (iii) rats after immunotoxic lesions of defined neuronal populations. In the unmanipulated brain QC was exclusively expressed by neurons and localized to the endoplasmatic reticulum, Golgi apparatus and secretory granules, consistent with a QC function in neuronal protein maturation and/or modification. However, in different neuronal lesion paradigms QC was also found to be induced in glial cells. So we observed astroglial QC expression associated with Abeta plaques in tg2576 mice. Moreover, following immunotoxic lesions of cholinergic and dopaminergic neurons in rat brain we detected astrocytic and microglial QC expression. Glial QC immunoreactivity was also observed in primary cultrures from mouse brain. Our results indicate that distinct kinds of lesions induce a differential glial response which involves QC expression and might, therefore, contribute to amyloidogenesis and inflammation. doi:10.1016/j.ijdevneu.2010.07.107 [P1.68] Ephrin-B1 reverse signaling controls a post-transcriptional feedback mechanism in neural progenitors D.N. Arvanitis 1,2 , T. Jungas 1,2 , A. Behar 1,2 , A. Davy 1,2,∗ 1
CNRS, France Universite de Toulouse, France Keywords: Ephrins; miRNAs; Cortical development; Neural progenitors 2
Eph receptors and ephrins exhibit complex and highly dynamic expression patterns during embryonic development. In addition, changes in their expression levels are often associated with pathological situations in adults. Yet, little is known on the mechanisms regulating their expression. Here we report that the expression