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  • 1. Darsalia, Vladimer
    et al.
    Mansouri, Shiva
    Ortsater, Henrik
    Olverling, Anna
    Nozadze, Nino
    Kappe, Camilla
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Tracy, Linda M.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Grankvist, Nina
    Sjöholm, Åke
    Patrone, Cesare
    Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats2012In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 122, no 9-10, p. 473-483Article in journal (Refereed)
    Abstract [en]

    Diabetes is a strong risk factor for premature and severe stroke. The GLP-IR (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto-Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 mu g/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2-4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-IR agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

  • 2. Kappe, Camilla
    et al.
    Tracy, Linda M.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Patrone, Cesare
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sjöholm, Åke
    GLP 1 secretion by microglial cells and decreased cns expression in obesity2012In: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 9, p. 276-Article in journal (Refereed)
    Abstract [en]

    Background: Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain. Methods: Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA. Results: We show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon. Conclusion: The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.

  • 3.
    Ramberg, Veronica
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Tracy, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Samuelsson, Malin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Nilsson, Lars N.G.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide2011In: Journal of Neuroinflammation, E-ISSN 1742-2094, Vol. 8, p. 34-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The transcription factors CCAAT/enhancer binding proteins (C/EBP) α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB). In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD) one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-β (Aβ) deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Aβ deposits with the aim of defining new therapeutic targets.

    METHODS:

    Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe) by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay.

    RESULTS:

    We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA binding activity to both C/EBP and κB sites is abolished after exposure to Aβ.

    CONCLUSIONS:

    These data suggest that both expression and function of C/EBPδ are dysregulated in Alzheimer's disease. C/EBPδ seems to be differently regulated in response to different conformations of Aβ. We propose that Aβ induces an imbalance between NF-κB and C/EBP transcription factors that may result in abnormal responses to inflammatory stimuli.

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  • 4.
    Tracy, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Neuroinflammation in Alzheimer’s disease and obesity2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) and obesity are both major problems in the western world. Although they may appear to have little in common at first glance, they are both characterized by chronic inflammation. Exactly how inflammation affects these disorders is far from clear. Microglia, the resident immune cells of the brain, can take on different phenotypes in response to inflammatory stimuli. They can become classically or alternatively activated, where they secrete pro- or anti-inflammatory cytokines respectively. The inflammatory response is to a large part regulated by transcription factors, such as C/EBPδ, which regulate gene expression. The aim of this thesis was to investigate 1) effects of the Alzheimer’s related peptide amyloid-β (Aβ) on C/EBPδ in astrocytes and microglia during inflammatory conditions, 2) how microglia is affected by elevated levels of free fatty acids (FFAs) occurring in obesity and 3) possible cellular sources of the neuroprotective peptide GLP-1 in the brain. In paper I we found that IL-1β-induced C/EBPδ appears to be blocked by Aβ fibrils but not Aβ oligomers in mixed glial cells. In paper II we found that the decreased levels of C/EBPδ were limited to astrocytes under inflammatory conditions and that there was no blocking of IL-1β-induced C/EBPδ in microglia. In paper III we found that the FFA palmitate induces an alternative activation in microglia with no effect on the expression of C/EBPδ or the pro-inflammatory cytokines TNF-α, IL-1β and IL-6. However, pre-exposure to palmitate potentiated microglia phagocytosis and changed the mRNA expression profile of some pro-inflammatory cytokines in response to inflammatory stimuli. In paper IV we found microglia to be a novel source of secreted GLP-1. Further, we found that the GLP-1 secretion could be decreased by inflammatory stimuli. In summary, the inflammatory response of C/EBPδ in AD appears to be disturbed. In addition, palmitate affects the response to inflammatory stimuli in microglia.

  • 5.
    Tracy, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bergqvist, Filip
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ivanova, Elena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jacobsen, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Exposure to the Saturated Free Fatty Acid Palmitate AltersBV-2 Microglia Inflammatory Response2013In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 3, p. 805-812Article in journal (Refereed)
    Abstract [en]

    Elevated levels of free fatty acids (FFAs) in plasma and increased incidence of chronic systemic inflammation are associated with obesity. In the brain, activated microglia are believed to play different roles during inflammation that may either be neuroprotective or promote neurodegeneration. Here, we have investigated the effects of FFAs on microglial response to inflammatory stimuli. Our results indicate that the saturated FFA palmitate on its own induces alternative activation of BV-2 microglia cells. Further, pre-exposure to palmitate changed the response of microglia to lipopolysaccharide (LPS). We show that palmitate affects the mRNA levels of the pro-inflammatory cytokines interleukin-1β and interleukin-6. The transcription factor CCAAT/enhancer-binding protein δ is also affected by pre-exposure to palmitate. Furthermore, the phagocytic activity of microglia was investigated using fluorescent beads. By analyzing the bead uptake by fluorescence-activated cell sorting, we found that palmitate alone, as well as together with LPS, stimulated the phagocytic activity of microglia. Taken together, our results suggest that exposure of microglia to increased levels of free fatty acids may alter the consequences of classical inflammatory stimuli.

  • 6.
    Tracy, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Strååt, Ylva
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ivanova, Elena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bergqvist, Filip
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Fibril-enriched amyloid-β inhibits interleukin-1 induced expression of the transcription factor C/EBPδ in astrocytes but not in microgliaManuscript (preprint) (Other academic)
1 - 6 of 6
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