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  • 1.
    Gustafsson, Helena
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Tamm, Christoffer
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Forsby, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Signalling pathways for insulin-like growth factor type 1-mediated expression of uncoupling protein 32004Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 88, nr 2, s. 462-468Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uncoupling protein 3 (UCP3) is a mitochondrial protein with antioxidant properties and its regulation by factors promoting cell-survival may be important for protection of, for instance, neurons in states of oxidative stress. In the present study, we investigated regulatory pathways for UCP3 expression mediated by the neuroprotective hormone insulin-like growth factor type 1 (IGF-1) in human neuroblastoma SH-SY5Y cells. Northern blot analysis and RT-PCR showed that treatment with 10 nm IGF-1 increased the UCP3 mRNA levels 2.5-fold after 5 h. Co-incubation with the phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 prohibited IGF-1-mediated induction of both UCP3 mRNA and protein in a concentration-dependent manner, with a complete blockage at 1 μm, as shown by RT-PCR and western blot analyses. The mitogen-activated protein (MAP) kinase kinase 1 (MKK1 or MEK) inhibitor PD98059 also decreased the UCP3 mRNA expression at 10 μm, however, this concentration only partly inhibited the protein expression. We conclude that IGF-1 enhanced UCP3 expression at transcriptional level, primarily through the PI3-kinase-dependent pathway and partly through the MAP kinase pathway.

  • 2.
    Heusser, Stephanie A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Yoluk, Özge
    Klement, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Riederer, Erika A.
    Lindahl, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Howard, Rebecca J.
    Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel2016Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, nr 2, s. 243-253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate-gated chloride channel (GluCl(cryst)) as a structurally accessible model for GABA(A) receptors. In contrast to native-like controls, GluCl(cryst) exhibits classical activation by its neurotransmitter ligand L-glutamate. The modified channel is also sensitive to allosteric modulators associated with human GABA(A) receptors, and to site-directed mutations predicted to alter channel opening.

  • 3.
    Holback, Sofia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Adlerz, Linda
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Iverfeldt, Kerstin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Increased processing of APLP2 and APP with concomitantformation of APP intracellular domains in BDNF and retinoic acid-differentiated human neuroblastoma cells2005Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 95, nr 4, s. 1059-1068Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. We have previously shown that all members of the APP protein family are up-regulated upon retinoic acid (RA)-induced neuronal differentiation of SH-SY5Y neuroblastoma cells. Here, we demonstrate that RA also affects the processing of APLP2 and APP, as shown by increased shedding of both sAPLP2 and sAPPalpha as well as elevated levels of the APP intracellular domains (AICDs). Brain-derived neurotrophic factor (BDNF) has been reported to induce APP promoter activity and RA induces expression of the tyrosine kinase receptor B (TrkB) in neuroblastoma cells. We show that the increase in shedding of both APLP2 and APP in response to RA is not mediated through the TrkB receptor. However, BDNF concomitant with RA increased the expression of APP even further. In addition, the secretion of sAPLP2 and sAPPalpha, as well as the levels of AICDs increased in response to BDNF. In contrast, the levels of membrane-bound APP C-terminal fragment C99 significantly decreased. Our results suggest that RA and BDNF shifts APP processing towards the alpha-secretase pathway. In addition, we show that RA and BDNF regulate N-linked glycosylation of APLP1.

  • 4. Johnson, Allan E.
    et al.
    Jeppsson, Fredrik
    Molecular Pharmacology, AstraZeneca R&D, Södertälje, Sweden.
    Svensson, Samuel P. S.
    AZD2184: a radioligand for sensitive detection of beta-amyloid deposits2009Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 108, nr 5, s. 1177-1186Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The presence of beta-amyloid plaques in brain is a hallmark of Alzheimer's disease (AD) and serves as a biomarker for confirmation of diagnosis postmortem. Positron emission tomography (PET) radioligands such as Pittsburgh compound B ([(11)C]-2-(3-fluoro-4-methylamino-phenyl)-benzothiazol-6-ol) (PIB) binds selectively to beta-amyloid and are promising new tools supporting the clinical diagnoses of AD. In addition, such methodology may be useful for evaluation of new drugs aiming at reduction of amyloid plaque load. The objective of this study is to develop a new amyloid selective PET radioligand with higher signal-to-background ratio when compared with existing amyloid PET ligands. The lead compound, AZD2184, (2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol) was found to have high affinity for amyloid fibrils in vitro (K(d): 8.4 +/- 1.0 nM). Two minutes after i.v. administration in rats, about 1% of the dose was in brain. In vitro autoradiography on cortical brain sections from amyloid-beta precursor protein/presenilin 1 (APP/PS1) mice and AD patients showed that while [(3)H]AZD2184 and [(3)H]PIB are mutually displaceable, [(3)H]AZD2184 displays a higher signal-to-background ratio primarily by virtue of lower background binding levels. The ratio of binding ability in prefrontal cortex (high plaque load) to subcortical white matter (background) was 4.5 for [(3)H]AZD2184 and 0.8 for [(3)H]PIB at 1 nM. In adjacent cortical sections from APP/PS1 mouse as well as from AD cortical tissue, [(3)H]AZD2184 and antibodies to human beta-amyloid labeled identical structures. In vivo administration of [(3)H]AZD2184 to APP/PS1 mice further showed that [(3)H]AZD2184 labels amyloid deposits with low non-specific background binding. Taken together, the pre-clinical profile of AZD2184 in relation to the reference ligand PIB, suggests that (11)C-labeled AZD2184 is a potential radioligand for PET-visualization of beta-amyloid deposits in the living human brain.

  • 5. Juréus, Anders
    et al.
    Jeppsson, Fredrik
    Department of Neuroscience, AstraZeneca R&D Södertälje, Södertälje, Sweden.
    Svensson, Samuel P. S.
    Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand2010Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 114, nr 3, s. 784-794Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Positron emission tomography (PET) radioligands that bind selectively to β-amyloid plaques (Aβ) are promising imaging tools aimed at supporting the diagnosis of Alzheimer’s disease and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use, there is a particular need for PET tracers labeled with fluorine-18, a radionuclide with 110 min half-life allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is, however, challenging because of the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high non-specific white matter binding. We have here developed the new benzofuran-derived radioligand containing fluorine, AZD4694 that shows high affinity for β-amyloid fibrils in vitro (Kd = 2.3 ± 0.3 nM). In cortical sections from human Alzheimer’s disease brain [3H]AZD4694 selectively labeled β-amyloid deposits in gray matter, whereas there was a lower level of non-displaceable binding in plaque devoid white matter. Administration of unlabeled AZD4694 to rat showed that it has a pharmacokinetic profile consistent with good PET radioligands, i.e., it quickly entered and rapidly cleared from normal rat brain tissue. Ex vivo binding data in aged Tg2576 mice after intravenous administration of [3H]AZD4694 showed selective binding to β-amyloid deposits in a reversible manner. In Tg2576 mice, plaque bound [3H]AZD4694 could still be detected 80 min after i.v. administration. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labeled AZD4694 may have potential for PET-visualization of cerebral β-amyloid deposits in the living human brain.

  • 6.
    Lundström, Linda
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Sollenberg, Ulla E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Bartfai, Tamas
    Langel, Ulo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Molecular characterization of the ligand binding site of the human galanin receptor type 2, identifying subtype selective interactions2007Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 103, nr 5, s. 1774-1784Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To define the specific role of the galanin receptors when mediating the effect of galanin, effective tools for distinct activation and inhibition of the different receptor subtypes are required. Several of the physiological effects modulated by galanin are implicated to be mediated via the GalR2 subtype and have been distinguished from GalR1 effects by utilizing the Gal(2–11) peptide, recognizing only GalR2 and GalR3. In this study, we have performed a mutagenesis approach on the GalR2 subtype and present, for the first time, a molecular characterization of the interactions responsible for ligand binding and receptor activation at this receptor subtype. Our results identify four residues, His252 and His253 located in transmembrane domain 6 and Phe264 and Tyr271 in the extracellular loop 3, to be of great significance. We show evidence for the N-terminal tail of GalR2 to participate in ligand binding and that selective binding of Gal(2–11) includes interaction with the Ile256 residue, located at the very top of TM 6. In conclusion, we present a mutagenesis study on GalR2 and confer interactions responsible for ligand binding and receptor activation as well as selective recognition of the Gal(2–11) peptide at this receptor subtype. The presented observations could be of major importance for the design and development of new and improved peptide and non-peptide ligands, selectively activating the GalR2 subtype.

  • 7. Mansouri, Shiva
    et al.
    Barde, Swapnali
    Ortsäter, Henrik
    Eweida, Mohamed
    Darsalia, Vladimer
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Sjöholm, Åke
    Hökfelt, Tomas
    Patrone, Cesare
    GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu2013Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 127, nr 2, s. 209-220Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 2 diabetes impairs adult neurogenesis which could play a role in the CNS complications of this serious disease. The goal of this study was to determine the potential role of galanin in protecting adult neural stem cells (NSCs) from glucolipotoxicity and to analyze whether apoptosis and the unfolded protein response were involved in the galanin-mediated effect. We also studied the regulation of galanin and its receptor subtypes under diabetes in NSCs in vitro and in the subventricular zone (SVZ) in vivo. The viability of mouse SVZ-derived NSCs and the involvement of apoptosis (Bcl-2, cleaved caspase-3) and unfolded protein response [C/EBP homologous protein (CHOP) Glucose-regulated protein 78/immunoglobulin heavy-chain binding protein (GRP78/BiP), spliced X-box binding protein 1 (XBP1), c-Jun N-terminal kinases (JNK) phosphorylation] were assessed in the presence of glucolipotoxic conditions after 24h. The effect of diabetes on the regulation of galanin and its receptor subtypes was assessed on NSCs in vitro and in SVZ tissues isolated from normal and type 2 diabetes ob/ob mice. We show increased NSC viability following galanin receptor (GalR)3 activation. This protective effect correlated with decreased apoptosis and CHOP levels. We also report how galanin and its receptors are regulated by diabetes in vitro and in vivo. This study shows GalR3-mediated neuroprotection, supporting a potential future therapeutic development, based on GalR3 activation, for the treatment of brain disorders.

  • 8. Ramesh Babu, J.
    et al.
    Lamar Seibenhener, M.
    Peng, Junmin
    Ström, Anna-Lena
    University of Kentucky, USA.
    Kemppainen, Robert
    Cox, Nancy
    Zhu, Haining
    Wooten, Michael C.
    Diaz-Meco, María T.
    Moscat, Jorge
    Wooten, Marie W.
    Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration2008Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 106, nr 1, s. 107-120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62(-/-) brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.

  • 9.
    Saar, Indrek
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. University of Tartu, Estonia .
    Lahe, Jaanus
    Langel, Kent
    Runesson, Johan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Webling, Kristin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Jaerv, Jaak
    Rytkonen, Jussi
    Narvanen, Ale
    Bartfai, Tamas
    Kurrikoff, Kaido
    Langel, Ülo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. University of Tartu, Estonia.
    Novel systemically active galanin receptor 2 ligands in depression-like behavior2013Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 127, nr 1, s. 114-123Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide galanin and its three G-protein coupled receptors, galanin receptor type 1-galanin receptor type 3 (GalR1-GalR3), are involved in the regulation of numerous physiological and disease processes, and thus represent tremendous potential in neuroscience research and novel drug lead development. One of the areas where galanin is involved is depression. Previous studies have suggested that activation of GalR2 leads to attenuation of depression-like behavior. Unfortunately, lack of in vivo usable subtype specific ligands hinders testing the role of galanin in depression mechanisms. In this article, we utilize an approach of increasing in vivo usability of peptide-based ligands, acting upon CNS. Thus, we have synthesized a series of novel systemically active galanin analogs, with modest preferential binding toward GalR2. We have shown that specific chemical modifications to the galanin backbone increase brain levels upon i.v. injection of the peptides. Several of the new peptides, similar to a common clinically used antidepressant medication imipramine, exerted antidepressant-like effect in forced swim test, a mouse model of depression, at a surprisingly low dose range (<0.5mg/kg). We chose one of the peptides, J18, for more thorough study, and showed its efficacy also in another mouse depression model (tail suspension test), and demonstrated that its antidepressant-like effect upon i.v. administration can be blocked by i.c.v. galanin receptor antagonist M35. The effect of the J18 was also abolished in GalR2KO animals. All this suggests that systemically administered peptide analog J18 exerts its biological effect through activation of GalR2 in the brain. The novel galanin analogs represent potential drug leads and a novel pharmaceutical intervention for depression.

  • 10.
    Ström, Anna-Lena
    et al.
    University of Kentucky, USA.
    Gal, Jozsef
    Shi, Ping
    Kasarskis, Edward J.
    Hayward, Lawrence J.
    Zhu, Haining
    Retrograde axonal transport and motor neuron disease2008Ingår i: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 106, nr 2, s. 495-505Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transport of material between extensive neuronal processes and the cell body is crucial for neuronal function and survival. Growing evidence shows that deficits in axonal transport contribute to the pathogenesis of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we review recent data indicating that defects in dynein-mediated retrograde axonal transport are involved in ALS etiology. We discuss how mutant copper-zinc superoxide dismutase (SOD1) and an aberrant interaction between mutant SOD1 and dynein could perturb retrograde transport of neurotrophic factors and mitochondria. A possible contribution of axonal transport to the aggregation and degradation processes of mutant SOD1 is also reviewed. We further consider how the interference with axonal transport and protein turnover by mutant SOD1 could influence the function and viability of motor neurons in ALS.

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