| 1. |
- Lindquist, Catarina, et al.
(författare)
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Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - 1044-7431 .- 1095-9327. ; 24:1, s. 250-257
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Tidskriftsartikel (refereegranskat)abstract
- Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 muM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 muM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 muM THIP plus 1 muM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 AM) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 2. |
- Parmar, Malin, et al.
(författare)
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A transplantation study of expanded human embryonic forebrain precursors: evidence for selection of a specific progenitor population
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 23:4, s. 531-543
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem and progenitor cells can be expanded under growth factor stimulation in vitro. It is likely that different mitogens and different culturing techniques selectively expand specific subclasses of cells, but this selection has not been well studied. We have expanded human cells isolated from the lateral ganglionic eminence (LGE) of a 10-week-old embryo in the presence of serum and epidermal growth factor. We provide evidence that culturing in this manner favors expansion of cells with characteristics similar to a subpopulation of LGE cells, the olfactory bulb progenitors, as revealed by their expression of Er81 in vitro. After transplantation into neonatal rats, the cells displayed similar properties to endogenous olfactory bulb progenitors when exposed to local cues present in the subventricular zone (SVZ) and rostral migratory stream (RMS). However, the human LGE cells do not migrate or undergo region-specific differentiation when placed outside the SVZ and RMS.
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| 3. |
- Trapp, T, et al.
(författare)
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Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1044-7431 .- 1095-9327. ; 23:2, s. 302-313
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Tidskriftsartikel (refereegranskat)abstract
- X-chromosome linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis protein (IAP) family and known to inhibit death of various cells under different experimental conditions. Although present in brain tissue, little is known about the physiology of the IAPs in nerve cells. Here we report on the establishment of transgenic mice with overexpression of human XIAP in brain neurons. The mice developed normally, and were more resistant to brain injury caused by transient forebrain ischemia after occlusion of the middle cerebral artery compared to control mice. The XIAP transgenic animals exhibited significantly smaller brain damage, as shown by TUNEL labelling, less reduction in brain protein synthesis, and less active caspase-3 after ischemia compared with controls. Upregulation of RhoB, which is an early indicator of neurological damage, was markedly reduced in the XIAP-overexpressing mice, which had also a better neurological outcome than control animals. This together with the increase in XIAP in normal mouse brain in regions surviving the infarct demonstrates that XIAP is an important factor promoting neuronal survival after ischemia. The results suggest that interference with the levels and the activity of XIAP in neurons may provide targets for the development of drugs limiting neuronal death after ischemia, and possibly in other brain injuries. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 4. |
- Yu, L Y, et al.
(författare)
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Regulation of sympathetic neuron and neuroblastoma cell death by XIAP and its association with proteasomes in neural cells
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1044-7431 .- 1095-9327. ; 22:3, s. 308-318
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Tidskriftsartikel (refereegranskat)abstract
- XIAP (X chromosome-linked inhibitor of apoptosis protein) has been shown to inhibit cell death in a variety of cells. XIAP binds to active caspases, but XIAP also has a carboxy-terminal RING domain that can regulate cell death via protein degradation. Here we have studied the function of full-length and RING-deleted XIAP in mouse sympathetic neurons microinjected with expression plasmids and in neuroblastoma cells stably overexpressing these proteins. Both full-length and RING-deleted XIAP-protected sympathetic neurons against death induced by nerve growth factor (NGF) withdrawal to about the same extent. However, the two proteins were differentially localized in transfected neurons, with RING-deleted XIAP present in the cytoplasm and full-length XIAP found mostly in cytoplasmic protein aggregates, as revealed by transmission electron microscopy. The occurrence of these aggregates was blocked by lactacystin, a proteasome inhibitor. In neuroblastoma cells, RING-deleted XIAP protected against death induced by staurosporine, thapsigargin, or serum withdrawal, whereas full-length XIAP was without effect. Full-length, but not RING-deleted, XIAP was degraded and ubiquitinated in the neuroblastoma cells. The results show that the presence of the RING domain differentially affected the neuroprotective ability of XIAP in sensory neurons and neuroblastoma cells. The RING domain was essentially required for the proteasomal association of XIAP and for its ubiquitination. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 5. |
- Agholme, Lotta, et al.
(författare)
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Low-dose γ-secretase inhibition increases secretion of Aβ peptides and intracellular oligomeric Aβ.
- 2017
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Ingår i: Molecular and cellular neurosciences. - : Elsevier BV. - 1095-9327 .- 1044-7431. ; 85, s. 211-219
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibitors have been considered promising drug candidates against Alzheimer's disease (AD) due to their ability to reduce amyloid-β (Aβ) production. However, clinical trials have been halted due to lack of clinical efficacy and/or side effects. Recent in vitro studies suggest that low doses of γ-secretase inhibitors may instead increase Aβ production. Using a stem cell-derived human model of cortical neurons and low doses of the γ-secretase inhibitor DAPT, the effects on a variety of Aβ peptides were studied using mass spectrometry. One major focus was to develop a novel method for specific detection of oligomeric Aβ (oAβ), and this was used to study the effects of low-dose γ-secretase inhibitor treatment on intracellular oAβ accumulation. Low-dose treatment (2 and 20nM) with DAPT increased the secretion of several Aβ peptides, especially Aβx-42. Furthermore, using the novel method for oAβ detection, we found that 2nM DAPT treatment of cortical neurons resulted in increased oAβ accumulation. Thus, low dose-treatment with DAPT causes both increased production of long, aggregation-prone Aβ peptides and accumulation of intracellular Aβ oligomers, both believed to contribute to AD pathology.
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| 6. |
- Agholme, Lotta, et al.
(författare)
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Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
- 2014
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier. - 1044-7431 .- 1095-9327. ; 58, s. 29-39
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.
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| 7. |
- Althini, Susanna, et al.
(författare)
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Blocked MAP kinase activity selectively enhances neurotrophic growth responses
- 2004
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 25:2, s. 345-354
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) 4 and 6 as well as MEK inhibitors PD98059 and U0126 potentiate neurotrophin 3 (NT3)- and neurturin (NTN)-induced neurite outgrowth and survival of peripheral neurons from the E9 chicken embryo. Preexposure to BMP4 or PD98059 was sufficient to prime the potentiation of subsequently added NT3. Phosphorylation of Erk2, induced by NT3, was reduced by MEK inhibition but unaffected by BMP signaling. Real-time PCR showed that neither BMP stimulation nor MEK inhibition increased Trk receptor expression and that the BMP-induced genes Smad6 and Id1 were not upregulated by PD98059. In contrast, both MEK inhibition and BMP signaling suppressed transcription of the serum-response element (SRE)-driven Egr1 gene. A reporter assay using NGF-stimulated PC12 cells demonstrated that MEK/Erk/Elk-driven transcriptional activity was inhibited by Smad1/5 and by PD98059. Thus, suppression of SRE-controlled transcription represents a likely convergence point for pathways regulating neurotrophic responses.
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| 8. |
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| 9. |
- Andrae, Johanna, et al.
(författare)
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Platelet-derived growth factor receptor-alpha in ventricular zone cells and in developing neurons.
- 2001
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Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 17:6
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Tidskriftsartikel (refereegranskat)abstract
- Cells in the early neuroepithelium differentiate and give rise to all cells in the central nervous system (CNS). The ways from a multipotent CNS stem cell to specialized neurons and glia are not fully understood. Using immunohistochemistry we found that neuroepithelial cells express the platelet-derived growth factor receptor-alpha (PDGFR-alpha) in the neural plate at embryonic day 8.5 and onwards in the neural tube. The protein was polarized to ventricular endfeet. Furthermore, PDGFR-alpha expression was localized to cells undergoing early neuronal development. We also found PDGFR-alpha expression in developing granule cells in the postnatal cerebellum, in Purkinje cells in the adult cerebellum and on processes of developing dorsal root ganglion cells. Previous reports mainly describe PDGFR-alpha expression in oligodendrocyte precursors and glial cells. We believe, in line with a few previous reports, that the PDGFR-alpha in addition marks a pool of undifferentiated cells, which are able to differentiate into neurons.
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| 10. |
- Ansell - Schultz, Anna, et al.
(författare)
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Reduced retromer function results in the accumulation of amyloid-beta oligomers
- 2018
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Ingår i: Molecular and Cellular Neuroscience. - : Academic Press. - 1044-7431 .- 1095-9327. ; 93, s. 18-26
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimers disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oA beta) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oA beta, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oA beta to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oA beta and in cells receiving oA beta from donor cells. We demonstrate that reduced retromer function increases oA beta accumulation in both cell systems, both the number of cells containing intracellular oA beta and the amount within them. This effect was shown at different time points and regardless if the AD originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oA beta accumulation, but oA beta treatment alone also lead to a reduction of VPS35 protein content. The accumulated oA beta seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oA beta received through different routes resulting in the accumulation of oA beta. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.
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