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| 2. |
- Kairisalo, Minna, et al.
(author)
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NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein.
- 2009
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In: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 30:6, s. 958-66
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Journal article (peer-reviewed)abstract
- X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element-binding protein. The mechanism involved nuclear factor-kappaB (NF-kappaB) activation and blocking of NF-kappaB signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)-6, which is an NF-kappaB-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-kappaB in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL-6 and XIAP interconnected via the NF-kappaB system.
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| 3. |
- Korhonen, Laura, et al.
(author)
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Bcl-2 regulates the levels of the cysteine proteases ICH and CPP32/Yama in human neuronal precursor cells
- 1997
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In: European Journal of Neuroscience. - Univ Uppsala, Ctr Biomed, Dept Dev Neurosci, S-75123 Uppsala, Sweden. : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 9:11, s. 2489-2496
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Journal article (peer-reviewed)abstract
- Members of the Bcl‐2 family are major regulators of cell death and survival. Bcl‐2 has been shown to heterodimerize with the death‐inducing protein Bax, but the mechanism of action of Bcl‐2 is not fully understood. Here we show, using the human NT‐2 neuronal cell line, that overexpression of Bcl‐2 leads to dramatic down‐regulation of the cysteine proteases ICH and CPP32/Yama, which are directly involved in cell death. In addition, the nuclear enzyme poly(ADP‐ribose) polymerase was cleaved in control cells but not in cells overexpressing Bcl‐2 following induction of apoptosis. The mRNA levels of ICH and CPP32/Yama were differentially affected by Bcl‐2 overexpression, suggesting both transcriptional and post‐transcriptional effects of the protein. These results demonstrate novel mechanisms of action of Bcl‐2 in influencing the expression of death effectors such as the cysteine proteases. The relative levels of Bcl‐2 and of various cysteine proteases ultimately determine survival and death of different cells, including neurons.
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| 4. |
- Korhonen, Laura, et al.
(author)
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Expression of c-Met in developing rat hippocampus : evidence for HGF as a neurotrophic factor for calbindin D-expressing neurons
- 2000
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In: European Journal of Neuroscience. - Uppsala Univ, Dept Neurosci Neurobiol, S-75123 Uppsala, Sweden. Univ Kuopio, AI Virtanen Inst, FIN-70211 Kuopio, Finland. Univ Cologne, Inst Pathol, D-50924 Cologne, Germany. : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 12:10, s. 3453-3461
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Journal article (peer-reviewed)abstract
- Hepatocyte growth factor-scatter factor (HGF) is expressed in different parts of the nervous system, and has been shown to exhibit neurotrophic activity. Here we show that c-Met, the receptor for HGF, is expressed in developing rat hippocampus, with the highest levels during the first postnatal weeks. To study the function of HGF, hippocampal neurons were prepared from embryonic rats and treated with different HGF concentrations. In these cultures, HGF increased the number of neurons expressing the 28-kDa calcium-binding protein (calbindin D) in a dose-dependent manner. The effect of HGF was larger than that observed with either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), and cotreatment of the cultures with HGF and the neurotrophins was additive with respect to calbindin D neurons. Besides affecting the number of neurons, HGF significantly increased the degree of sprouting of calbindin D-positive neurons, suggesting an influence on neuronal maturation. BDNF and NT-3 stimulated neurite outgrowth of calbindin D neurons to a much smaller degree. In contrast to calbindin D neurons, HGF did not significantly increase the number of neurons immunoreactive with the neurotransmitter gamma-aminobutyric acid (GABA) in the hippocampal cultures. Immunohistochemical studies showed that c-Met-, calbindin D- and HGF-immunoreactive cells are all present in the dentate gyrus and partly colocalize within neurons. These results show that HGF acts on calbindin D-containing hippocampal neurons and increases their neurite outgrowth, suggesting that HGF plays an important role for the maturation and function of these neurons in the hippocampus.
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| 5. |
- Korhonen, Laura, 1974-, et al.
(author)
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Increase in Bcl-2 phosphorylation and reduced levels of BH3-only Bcl-2 family proteins in kainic acid-mediated neuronal death in the rat brain
- 2003
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In: European Journal of Neuroscience. - : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 18:5, s. 1121-1134
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Journal article (peer-reviewed)abstract
- Kainic acid induces excitotoxicity and nerve cell degeneration in vulnerable regions of rat brain, most markedly in hippocampus and amygdala. Part of the cell death following kainic acid is apoptotic as shown by caspase 3 activation and chromatin condensation. Here we have studied the regulation of pro- and anti-apoptotic proteins belonging to the Bcl-2 family in rat hippocampus and amygdala by kainic acid in relationship to ensuing neuronal death. The pro-apoptotic protein Bax was up-regulated in hippocampus 6 h after kainic acid administration. The increase in Bax was followed by the appearance of TdT-mediated dUTP nick end label ling-positive cells which were prominent at 24 h. Immunohistochemistry for active Bax revealed a punctated labelling of neurons in the CA3 and hilar regions of hippocampus as well as in amygdala. Double staining for NeuN, a marker for nerve cells, and TdT-mediated dUTP nick end labelling showed that mainly neurons undergo degeneration after kainic acid treatment. In contrast to Bax, the pro-apoptotic BH3-only Bcl-2 proteins Bim and Harakiri/DP5 were down-regulated by kainic acid. This was also observed for the anti-apoptotic proteins Bcl-x and Bcl-w. Immunoreactive Bcl-2 was up-regulated in hippocampus after kainic acid together with an increase in the phosphorylation of serine-87 in Bcl-2, suggesting a post-transcriptional modification of the protein. This was confirmed using immunoprecipitation of total Bcl-2 from hippocampus and amygdala which revealed an increase in serine-87 phospho-Bcl-2 after kainic acid. Inhibition of the c-jun N-terminal protein kinase pathway reduced both serine-87 phosphorylation and cell death after kainic acid. This indicates an important role of Bcl-2 phosphorylation in controlling neuronal death after kainic acid. In contrast to the situation in trophic factor-deprived neurons, no up-regulation of Bim or Harakiri/DP5 proteins occurred after kainic acid, suggesting alternative pathways for regulation of cell death in excitotoxicity The results indicate that not only the relative levels of Bcl-2 family proteins but also conformation changes and post-translational modifications contribute to neuronal death following kainic acid.
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| 6. |
- Makela, Johanna, et al.
(author)
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Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mediates neuroprotection against excitotoxic brain injury in transgenic mice : role of mitochondria and X-linked inhibitor of apoptosis protein
- 2016
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In: European Journal of Neuroscience. - : WILEY. - 0953-816X .- 1460-9568. ; 43:5, s. 626-639
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Journal article (peer-reviewed)abstract
- Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1 in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1 in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1 transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC-1 transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48h in wild-type mice but significantly less so in PGC-1 transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1 overexpression can induce a delay in cell death. Immunoblotting showed that X-linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1 transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1 overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP.
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| 7. |
- Putkonen, Noora, et al.
(author)
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Involvement of cyclin-dependent kinase-5 in the kainic acid-mediated degeneration of glutamatergic synapses in the rat hippocampus
- 2011
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In: European Journal of Neuroscience. - : WILEY-BLACKWELL. - 0953-816X .- 1460-9568. ; 34:8, s. 1212-1221
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Journal article (peer-reviewed)abstract
- Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin-dependent kinase-5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)-induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA-mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post-synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2-bis(o-aminophenoxy)ethane-N,N,N?',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and glycol-bis (2-aminoethylether)-N,N,N?',N?'-tetra-acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant-negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant-negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA-mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases.
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| 8. |
- Takei, Nobuyuki, et al.
(author)
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Pituitary adenylate cyclase-activating polypeptide promotes the survival of basal forebrain cholinergic neurons in vitro and in vivo : comparison with effects of nerve growth factor
- 2000
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In: European Journal of Neuroscience. - Uppsala Univ, BMC, Dept Neurosci, S-75123 Uppsala, Sweden. Univ Cambridge, MRC, Cambridge Ctr Brain Repair, Cambridge CB2 1TN, England. Osaka Univ, Inst Prot Res, Div Prot Biosynth, Suita, Osaka 565, Japan. German Canc Res Ctr, D-69120 Heidelberg, Germany. : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 12:7, s. 2273-2280
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Journal article (peer-reviewed)abstract
- Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasointestinal polypeptide gene family for which neurotrophic activity has been postulated. PACAP mRNA is expressed in the developing and adult hippocampus, which is the principal target region of septal cholinergic neurons. We therefore studied the effects of PACAP on septal cholinergic neurons. In primary cultures from septum of embryonic and postnatal rats, PACAP increased the number of neurons immunohistochemically stained for the low-affinity nerve growth factor (NGF) receptor p75 and for the enzyme choline acetyltransferase (ChAT). PACAP also caused a corresponding increase in ChAT activity. In comparison, NGF had a greater effect than PACAP on the number of p75- and ChAT-positive neurons in these cultures. In vivo, following fimbria fornix transection, the number of immunohistochemically stained septal cholinergic neurons fell significantly to 18% in rats given continuous intracerebroventricular infusion of vehicle, whereas in rats given NGF the number of these neurons did not differ significantly from unoperated controls. In PACAP-treated rats the number was 48% of unoperated values, which represented a significant increase compared with vehicle-treated rats and a significant decrease compared with NGF-treated rats or unoperated controls. Double-staining experiments revealed that most ChAT-positive neurons in rat medial septum also express PACAP receptor 1. Together the results show that PACAP promotes the survival of septal cholinergic neurons in vitro, and after injury in vivo, suggesting that PACAP acts as a neurotrophic factor influencing the development and maintenance of these neurons.
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| 9. |
- Zhu, Changlian, 1964, et al.
(author)
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X chromosome-linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia-ischemia through up-regulation of mitochondrial antioxidants.
- 2007
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In: The European journal of neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 26:12, s. 3402-10
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Journal article (peer-reviewed)abstract
- We demonstrate that X chromosome-linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease-related models of brain injury, hypoxia-ischemia and irradiation, as judged by lower expression of nitrotyrosine (5-fold) and 4-hydroxy-2-nonenal (10-fold) in XIAP-overexpressing compared with wild-type mice. XIAP overexpression induced up-regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP-overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up-regulation of mitochondrial antioxidants. XIAP-induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia-ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
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