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  • 1. Aho, Leena
    et al.
    Karkola, Kari
    Juusela, Jari
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Heavy alcohol consumption and neuropathological lesions: a post-mortem human study2009In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 87, no 12, 2786-2792 p.Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

  • 2. Alfonso, Julieta
    et al.
    Pollevick, Guido
    Castensson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frasch, Alberto
    Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, no 2, 225-34 p.Article in journal (Refereed)
    Abstract [en]

    In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library. mRNA amounts were quantified using a Real Time PCR SYBR Green assay. We found that, in general, individuals from an inbred rat population (n = 20) have shown 2-3 times differences in the basal level of expression of the genes analyzed. Up to several fold differences among individuals were observed for certain genes. These inter-individual differences were obtained after correction for the different amounts of mRNA in each sample. Power calculations were performed to determine the number of individuals required to detect reliable differences in expression levels between a control and an experimental group. These data indicated that, depending on the variability of the candidate gene selected, it was necessary to analyze from five to 135 individuals in each group to detect differences of 50% in the levels of mRNA expression between two groups investigated. The comparison of mRNA abundance from different genes revealed a wide range of expression levels for the 37 genes, showing a 26,000-fold difference between the highest and lowest expressed gene.

  • 3.
    Althini, Sanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bengtsson, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Usoskin, Dmitry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Söderström, Stine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Lindqvist, Eva
    Chuva de Sousa Lopes, Susana
    Olson, Lars
    Lindeberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Normal Nigrostriatal Innervation but Dopamine Dysfunction in Mice Carrying Hypomorphic Tyrosine Hydroxylase Alleles2003In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 72, no 4, 444-453 p.Article in journal (Refereed)
    Abstract [en]

    We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3' untranslated region of TH. An frt-flanked neomycin-resistance (neo(r)) cassette was placed in the 3' end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neo(r) cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neo(r)-positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neo(r) cassette from the knock-in alleles partially restored TH and dopamine levels. The present neo(r)-positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism.

  • 4.
    Brännvall, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svahn, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix2007In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 85, no 10, 2138-2146 p.Article in journal (Refereed)
    Abstract [en]

    Efficient 3D cell systems for neuronal induction are needed for future use in tissue regeneration. In this study, we have characterized the ability of neural stem/progenitor cells (NS/PC) to survive, proliferate, and differentiate in a collagen type I-hyaluronan scaffold. Embryonic, postnatal, and adult NS/PC were seeded in the present 3D scaffold and cultured in medium containing epidermal growth factor and fibroblast growth factor-2, a condition that stimulates NS/PC proliferation. Progenitor cells from the embryonic brain had the highest proliferation rate, and adult cells the lowest, indicating a difference in mitogenic responsiveness. NS/PC from postnatal stages down-regulated nestin expression more rapidly than both embryonic and adult NS/PC, indicating a faster differentiation process. After 6 days of differentiation in the 3D scaffold, NS/PC from the postnatal brain had generated up to 70% neurons, compared with 14% in 2D. NS/PC from other ages gave rise to approximately the same proportion of neurons in 3D as in 2D (9-26% depending on the source for NS/PC). In the postnatal NS/PC cultures, the majority of III-tubulin-positive cells expressed glutamate, -aminobutyric acid, and synapsin I after 11 days of differentiation, indicating differentiation to mature neurons. Here we report that postnatal NS/PC survive, proliferate, and efficiently form synapsin I-positive neurons in a biocompatible hydrogel.

  • 5.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Limbach, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
    Colman, David R.
    Svenningsen, Åsa Fex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion?2010In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 88, no 11, 2338-2349 p.Article in journal (Refereed)
    Abstract [en]

    During embryonic development of the peripheral nervous system (PNS), the adhesion molecule neuronal cadherin (N-cadherin) is expressed by Schwann cell precursors and associated with axonal growth cones. N-cadherin expression levels decrease as precursors differentiate into Schwann cells. In this study, we investigated the distribution of N-cadherin in the developing postnatal and adult rat peripheral nervous system. N-cadherin was found primarily in ensheathing glia throughout development, concentrated at neuron glial or glial glial contacts of the sciatic nerve, dorsal root ganglia (DRG), and myenteric plexi. In the sciatic nerve, N-cadherin decreases with age and progress of myelination. In adult animals, N-cadherin was found exclusively in nonmyelinating Schwann cells. The distribution of N-cadherin in developing E17 DRG primary cultures is similar to what was observed in vivo. Functional studies of N-cadherin in these cultures, using the antagonist peptide INPISGQ, show a disruption of the attachment between Schwann cells, but no interference in the initial or long-term contact between Schwann cells and axons. We suggest that N-cadherin acts primarily in the adhesion between glial cells during postnatal development. It may form adherents/junctions between nonmyelinating glia, which contribute to the stable tubular structure encapsulating thin caliber axons and thus stabilize the nerve structure as a whole.

  • 6.
    Corell, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wicher, Grzegorz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Radomska, Katarzyna J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Dağlıkoca, E Duygu
    Godskesen, Randi Elberg
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedikz, Eirikur
    Magnaghi, Valerio
    Fex Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination2015In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 2, 285-295 p.Article in journal (Refereed)
    Abstract [en]

    The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.

  • 7.
    Forsberg-Nilsson, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Behar, T
    Afrakhte, Mozhgan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Barker, J
    McKay, R
    Platelet-derived growth factor induces chemotaxis of neuroepithelial stem cells1998In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 53, no 5, 521-530 p.Article in journal (Refereed)
    Abstract [en]

    The ability of differentiating cells to migrate within the developing central nervous system (CNS) depends on extrinsic guidance signals, some of which are growth factors. In this study we have investigated the chemotactic response of cultured stem cells from the embryonic rat cortex to platelet-derived growth factor (PDGF). Nestin-positive stem cells from the developing CNS can be maintained and expanded in vitro under serum-free conditions in the presence of basic fibroblast growth factor (bFGF). Northern blot analysis of PDGF receptor expression revealed both α- and β-receptors on bFGF-treated neural stem cells. Both PDGF-AA and PDGF-BB readily induced directed migration of cultured neuroepithelial cells as measured in a microchemotaxis assay. Blocking of the migratory response was achieved by incubation with PDGF isoform-specific antibodies. More than 90% of the migrating cells were nestin-positive and incorporation of BrdU was also seen suggesting the cells to be immature and not yet committed to a specific cell lineage. These findings suggest a role for PDGF in cell migration in the developing cortex.

  • 8. Hallböök, F
    et al.
    Persson, H
    Barbany, G
    Ebendal, T
    Development and regional expression of chicken neuroleukin (glucose-6-phosphate isomerase) messenger RNA.1989In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 23, no 2, 142-51 p.Article in journal (Refereed)
    Abstract [en]

    Neuroleukin (NLK) is a protein identical with the glycolytic enzyme glucose-6-phosphate isomerase (GPI) that has been reported to support the survival of a subpopulation of neurons in embryonic dorsal root ganglia and spinal cord neurons in culture. In this report we have studied the developmental expression of NLK mRNA in the chick embryo in order to evaluate its possible role as a neurotrophic factor. The chicken gene encoding NLK was isolated by cross-hybridization to a mouse NLK cDNA clone. A DNA fragment from the chicken NLK gene with a 90% nucleotide sequence homology to mouse NLK cDNA encoding amino acids 310-355 was then used as a hybridization probe in a series of RNA-blots. In the entire embryo NLK mRNA was found already at embryonic day 3.5 (E3.5) and the level of expression was significantly decreased between E3.5 and hatching. Roughly similar levels of NLK mRNA were found in all tissues of the E8 embryo analyzed with the exception of the brain, which contained only low levels. When the developmental expression was analyzed in different tissues separately, NLK mRNA expression was found to decrease during development in the heart and bursa of Fabricius, whereas the level of mRNA in the brain showed a large increase shortly after hatching. The spinal cord and the pectoral and femoral muscles all showed high levels of NLK mRNA throughout development. In the adult chick, the highest levels of NLK mRNA were found in the muscle, brain, and kidney, where the NLK mRNA was estimated to account for approximately 0.1% of the total mRNA in these tissues. A widespread expression of NLK mRNA was observed in the adult brain with approximately similar levels in all brain regions tested. Similar results were also obtained when NLK mRNA expression was analyzed in adult rats. Our results show that developmental expression of the NLK gene is independently regulated in different tissues. The widespread and abundant expression of both the avian and rodent NLK gene is in accordance with its newly discovered identity as a glycolytic enzyme. Consequently, the developmental and adult pattern of NLK mRNA expression does not favour a specific trophic role for this protein in accordance with other known neurotrophic factors.

  • 9.
    Israelsson, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bjorklund, Ulf
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Anti-inflammatory treatment of traumatic brain injury with Rabeximod reduces cerebral antigen presentation in mice2015In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 10, 1519-1525 p.Article in journal (Refereed)
    Abstract [en]

    A major component of the damaging effect after traumatic brain injury (TBI) is activation of the inflammatory system. In particular, chemokines and chemokine-regulated factors become activated in resident brain cells and signal to different invading immune cells. For evaluation of the effect on invading cells 3 days after injury, mice were treated with a single initial dose of the anti-inflammatory agent Rabeximod in an experimental TBI model. For comparison, mice subjected to TBI were similarly injected with cyclophosphamide. TBI resulted in reduced body weight, an effect further enhanced by administration of Rabeximod, without obvious influence on motor performance. As revealed by quantitative RT-PCR, microglial upregulation of chemokine Ccl3 in response to TBI was unaffected by Rabeximod. Also, injury-induced expression of Cxcl10 in plasmacytoid dendritic cells (DCs) and endothelial expression of platelet selectin (Selp) were uninfluenced by Rabeximod. In contrast, Rabeximod robustly reduced the H2-Aa transcript characteristic for classical DCs defined by CD11c/Itgax in the injured brain. In addition, the expression of lysozyme 2 in large phagocytic cells was impaired by Rabeximod. These results show that Rabeximod exerts a selective and potent inhibition of cells serving cortical antigen presentation after brain trauma.

  • 10.
    Israelsson, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. Neurosci.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Neurokirurgi.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. neurosci.
    Usoskin, Dmitry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. Neurosci.
    Althini, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. neurosci.
    Lindeberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. neurosci.
    Deng, Chu-Xia
    Fukuda, Tomokazu
    Wang, Yun
    Kaartinen, Vesa
    Mishina, Yuji
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Neurokirurgi.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Develop. Neurosci.
    Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse2006In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 84, no 1, 47-57 p.Article in journal (Refereed)
    Abstract [en]

    Three genetic mouse models were examined to define effects of bone morphogenetic protein (BMP) signalling on gene expression in normal and injured adult brain. CaMKII-Cre eliminated the BMP receptor Acvr1 (Alk2) and the common TGF beta superfamily signal mediator Smad4 or activated a constitutively active Acvr1 in postnatal forebrain neurons. All mutants followed mendelian ratios, with no overt phenotypic changes. In situ hybridization demonstrated normal patterns of the dendritic marker MAP2 (Mtap2) throughout cortex despite neuron-specific losses of Acvr1 or Smad4. However, strong up-regulation of Mtap2 transcript in these mice was found by quantitative RT-PCR (qRT-PCR), indicating that Mtap2 is normally suppressed by BMR Traumatic brain injury (TBI) resulted in increases of histone-associated DNA fragments in both control and Smad4-deficient cortex. Several cell-type-specific transcripts known to be involved in injury-related responses were measured by qRT-PCR. Gfap mRNA was strongly upregulated in controls as well as in the loss-of-BMP-signalling mutants. Notably, activated Acvr1 signalling gave significantly lower TBI-induced up-regulations of Gfap and Phox2a mRNA levels, indicating reductions in astroglial and neuronal reactions to injury. Strong impairment in injury-induced Timp1 transcript up-regulation was also seen in these mice. In contrast, osteopontin (Spp1) transcript levels in activated microglia were not reduced by Acvr1 signalling. Altogether, the data suggest that BMP signalling is dispensable in adult cortical neurons but that augmented BMP signalling affects molecular changes associated with neuronal lesions.

  • 11.
    Kullander, Klas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Kylberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Specificity of neurotrophin-3 determined by loss-of-function mutagenesis1997In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 50, no 3, 496-503 p.Article in journal (Refereed)
    Abstract [en]

    Neurotrophin-3 (NT-3) is a member of the family of neurotrophic factors, which also includes nerve growth factor (NGF) and which have specific activities on different subsets of vertebrate neurons. The aim of this study was to determine which residues in NT-3 direct its specificity to the cognate TrkC receptor. It was possible to replace 80% of the residues in NT-3 with NGF residues without loss of specific activity. Residues D72, Y85, R87, W101, S107, and A111, together with either the residues F12, V18, V20, M37, V42, F54, and K57 or the variable regions IV and V, accounted for the specificity of NT-3. It is concluded that NGF and NT-3 use overlapping as well as separated regions for determination of specificities for their cognate receptors TrkA and TrkC, respectively.

  • 12.
    Lindeberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Mattsson, Ragnar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Timing the doxycycline yields different patterns of genomic recombination in brain neurons with a new inducible Cre transgene2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 68, no 2, 248-253 p.Article in journal (Refereed)
    Abstract [en]

    We have developed a transgenic mouse expressing the Cre recombinase under control of a tetracycline-responsive promoter. Using a CamKIIalpha-driven tTA transgenic strain and a lacZ reporter mouse, we obtained the expected neuronal pattern of recombination in the olfactory lobe, cortex, striatum, hippocampus and Purkinje cells. Moreover, recombination can be completely abolished by feeding the mice doxycycline in their drinking water. We also show that it is possible to get a different pattern of recombination by changing the timing of the doxycycline-mediated shutdown of Cre expression. By starting the doxycycline treatment at birth, we restrict recombination to striatum only. This approach should be applicable to other inducible transgenic strains, thus increasing the number of available tissue-specific patterns for conditional knockouts. Also, our tetO-Cre transgene can be combined with any of the increasing number of tetracycline transactivator transgenic strains to direct specifically inducible genomic recombination to several areas of the brain.

  • 13.
    Parrow, V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fagerström, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Meyerson, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nånberg, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Påhlman, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Protein kinase C-alpha and -epsilon are enriched in growth cones of differentiating SH-SY5Y human neuroblastoma cells1995In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 41, no 6, 782-791 p.Article in journal (Refereed)
    Abstract [en]

    SH-SY5Y cells differentiate into neuronal-like cells and express marker proteins like growth-associated protein (GAP-43) and neuropeptide tyrosine when treated with a low concentration (16 nM) of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of growth factors or serum. Both control and differentiated cells expressed protein kinase C-alpha (PKC-alpha), PKC-epsilon, and PKC-zeta as revealed by Western blot analyses, but the subcellular distribution of the three isoforms was not uniform, indicating specific localized functions of the enzymes. In growth cones prepared from differentiating cells PKC-alpha and PKC-epsilon were enriched. In contrast, PKC-zeta was more evenly distributed within the differentiating cell. Cells treated with a high concentration of TPA (1.6 microM) differentiate poorly and continue to proliferate. In those cells, PKC-alpha and PKC-epsilon were found to be down-regulated while PKC-zeta remained present. Thus, down-regulation of PKC-alpha and PKC-epsilon appears to be incompatible with neuronal differentiation of SH-SY5Y cells. These cells also differentiate when treated with a combination of basic fibroblast growth factor and insulin-like growth factor I. Growth cones isolated from such cells are also enriched in PKC-alpha and PKC-epsilon, but not in PKC-zeta. Based on the subcellular distribution of PKC-alpha and epsilon, and that PKC substrates like GAP-43 and pp60c-src are enriched in SH-SY5Y growth cones, a role during neurite growth is suggested.

  • 14.
    Schizas, Nikos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Andersson, Brittmarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hailer, Nils P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Interleukin-1 Receptor Antagonist Promotes Survival of Ventral Horn Neurons and Suppresses Microglial Activation in Mouse Spinal Cord Slice Cultures2014In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 92, no 11, 1457-1465 p.Article in journal (Refereed)
    Abstract [en]

    Secondary damage after spinal cord injury (SCI) induces neuronal demise through neurotoxicity and inflammation, and interleukin (IL)-1 beta is a key inflammatory mediator. We hypothesized that IL-1 beta is released in spinal cord slice cultures (SCSC) and aimed at preventing the potentially neurotoxic effects of IL-1 beta by using interleukin-1 receptor antagonist (IL1RA). We hypothesized that IL1RA treatment enhances neuronal survival and suppresses microglial activation. SCSC were cultured up to 8 days in vitro (DIV) in the presence of IL1RA or without, either combined with trophic support using neurotrophin (NT)-3 or not. Four groups were studied: negative control, IL1RA, NT-3, and IL1RA1NT-3. IL-1 beta concentrations in supernatants were measured by ELISA. SCSC were immunohistochemically stained for NeuN and a-neurofilament, and microglial cells were visualized with isolectin B-4. After 8 DIV, ventral horn neurons were significantly more numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Activated microglial cells were significantly less numerous in the IL1RA, NT-3, and IL1RA1NT-3 groups compared with negative controls. Axons expanded into the collagen matrix after treatment with IL1RA, NT-3, or IL1RA1NT-3, but not in negative controls. IL-1 beta release from cultures peaked after 6 hr and was lowest in the IL1RA1NT-3 group. We conclude that IL-1 beta is released in traumatized spinal cord tissue and that IL1RA could exert its neuroprotective actions by blocking IL-1-receptors. IL1RA thereby sustains neuronal survival irrespective of the presence of additional trophic support. Microglial activation is suppressed in the presence of IL1RA, suggesting decreased inflammatory activity. IL1RA treatment approaches may have substantial impact following SCI.

  • 15.
    Sundström Poromaa, Inger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Georgakis, Marios K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens, Greece.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sex differences in depression during pregnancy and the postpartum period2017In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 95, no 1-2, 719-730 p.Article, review/survey (Refereed)
    Abstract [en]

    Women have a lifetime risk of major depression double that of men but only during their reproductive years. This sex difference has been attributed partially to activational effects of female sex steroids and also to the burdens of pregnancy, childbirth, and parenting. Men, in contrast, have a reproductive period difficult to delineate, and research on the mental health of men has rarely considered the effects of fatherhood. However, the couple goes through a number of potentially stressing events during the reproductive period, and both mothers and fathers are at risk of developing peripartum depression. This Review discusses the literature on maternal and paternal depression and the endocrine changes that may predispose a person to depression at this stage of life, with specific focus on the hypothalamus-pituitary axis, oxytocin, and testosterone levels in men. Important findings on sex differences in the neural correlates of maternal and paternal behavior have emerged, highlighting the relevance of the emotional brain in mothers and the sociocognitive brain in fathers and pointing toward the presence of a common parents' brain. Additionally, sex differences in neurogenesis and brain plasticity are described in relation to peripartum depression.

  • 16. Söderström, S
    et al.
    Hallböök, F
    Ibáñez, C F
    Persson, H
    Ebendal, T
    Recombinant human beta-nerve growth factor (NGF): biological activity and properties in an enzyme immunoassay.1990In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 27, no 4, 665-77 p.Article in journal (Refereed)
    Abstract [en]

    Nerve growth factor (NGF) supports sympathetic and sensory neurons in the peripheral nervous system and also functions in the development and maintenance of cholinergic neurons in the basal forebrain. NGF distribution can be studied in the brain of the rat and mouse with the use of a sensitive two-site enzyme immunoassay (EIA) for mouse NGF. It would be of interest to measure the NGF protein also in the human brain, especially against the background that the cholinergic neurons are severely deteriorated in senile dementia of the Alzheimer type. The limited immunological cross-reactivity between NGFs from different species has previously hampered attempts to determine levels of the human NGF. We have now examined the biological activity and immunological properties of human recombinant NGF protein in medium conditioned by COS cells transfected with the human NGF gene. The human NGF behaved similar to mouse NGF in a sympathetic ganglion bioassay. The monoclonal antibody 27/21 to mouse NGF was shown to effectively block the activity of both the human recombinant NGF and mouse native NGF. A two-site EIA using monoclonal antibody 27/21 was optimized. Under the conditions used, the EIA detected the human recombinant NGF with the same sensitivity (1 pg/ml) as shown for the mouse NGF. It should now be possible to test this EIA also on homogenized tissue to examine human NGF in brain samples from Alzheimer patients and age-matched controls.

  • 17. Vogt, Cornelia
    et al.
    Hailer, Nils P.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ghadban, Chalid
    Korf, Horst-Werner
    Dehghani, Faramarz
    Successful inhibition of excitotoxic neuronal damage and microglial activation after delayed application of interleukin-1 receptor antagonist2008In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 86, no 15, 3314-21 p.Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-1 is an important mediator of neuronal demise and glial activation after acute central nervous system lesions and is antagonized by IL-1 receptor antagonist (IL-1RA). Here we determined the time window in which IL-1RA elicits neuroprotective effects in rat organotypic hippocampal slice cultures (OHSC). OHSC were lesioned with N-methyl-D-aspartate (NMDA) and treated with IL-1RA (100 ng/ml) at different time points postinjury or were left untreated. Damaged neurons, microglial cells, and astrocytes were labelled with NeuN, propidium iodide, isolectin B(4), or glial fibrillary acidic protein (GFAP), respectively, and were analyzed by confocal laser scanning microscopy. In lesioned OHSC, the most dramatic increase in microglial cell number occurred between 8 and 16 hr postinjury, and the maximal neuronal demise was found between 16 and 24 hr postinjury. The cellular source of IL-1beta was investigated by immunohistochemistry, and IL-1beta immunoreactivity was found in few microglial cells at 4 hr postinjury and in numerous microglial cells and astrocytes at 16 hr postinjury. In both glial populations, IL-1beta immunoreactivity peaked at 24 hr postinjury. IL-1RA treatment potently suppressed neuronal damage by 55% when initiated within the first 16 hr postinjury (P < 0.05), and IL-1RA treatment initiated at 24 hr postinjury resulted in weaker but still significant neuroprotection. IL-1RA treatment also reduced the number of microglial cells significantly when initiated within 36 hr postinjury (P < 0.05). In conclusion, IL-1RA exhibits significant neuroprotective effects in this in vitro model of excitotoxic injury even after delayed application.

  • 18.
    Wicher, Grzegorz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fex Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Gyllencreutz, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rask, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Aldskogius, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuroanatomy.
    Low density lipoprotein-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter2006In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 83, no 5, 864-873 p.Article in journal (Refereed)
    Abstract [en]

    Lipoprotein receptor-related protein-2 (LRP2)/megalin is a member of the low density lipoprotein receptor (LDLR) family, and is essential in absorptive epithelia for endocytosis of lipoproteins, low molecular weight proteins, cholesterol and vitamins, as well as in cellular signaling. Previous studies have shown megalin expression in ependymal cells and choroid plexus. We have investigated megalin expression in the spinal cord of postnatal mice with immunohistochemistry and immunoblot. Antibodies recognizing either the cytoplasmic tail (MM6) or the extracellular domain (E11) of megalin labeled oligodendrocytes in the spinal cord white matter, in parallel with myelination. MM6 antibodies, predominantly labeled the nuclei, whereas E11 antibodies labeled the cytoplasm of these cells. MM6 antibodies labeled also nuclei of oligodendrocytes cultured from embryonic mouse spinal cord. Immunoblots of spinal cord showed intact megalin, as well as its carboxyterminal fragment, the part remaining after shedding of the extracellular domain of megalin. Megalin-immunoreactive oligodendrocytes also expressed presenilin 1, an enzyme responsible for gamma-secretase mediated endodomain cleavage. These findings show that spinal cord oligodendrocytes are phenotypically different from those in the brain, and indicate that megalin translocates signals from the cell membrane to the nucleus of oligodendrocytes during the formation and maintenance of myelin of long spinal cord pathways.

1 - 18 of 18
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