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  • 1.
    Agalave, Nilesh M
    et al.
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Abdelmoaty, Sally
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Su, Jie
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Baharpoor, Azar
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Lundbäck, Peter
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Palmblad, Karin
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Ulf
    Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Harris, Helena
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis.2014Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 155, nr 9, s. 1802-1813Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. Subsequent to induction of collagen antibody-induced arthritis (CAIA), Hmgb1 mRNA and extranuclear protein levels were significantly increased in the lumbar spinal cord. Intrathecal (i.t.) injection of a neutralizing anti-HMGB1 monoclonal antibody or recombinant HMGB1 box A peptide (Abox), which each prevent extracellular HMGB1 activities, reversed CAIA-induced mechanical hypersensitivity. This occurred during ongoing joint inflammation as well as during the postinflammatory phase, indicating that spinal HMGB1 has an important function in nociception persisting beyond episodes of joint inflammation. Importantly, only HMGB1 in its partially oxidized isoform (disulfide HMGB1), which activates toll-like receptor 4 (TLR4), but not in its fully reduced or fully oxidized isoforms, evoked mechanical hypersensitivity upon i.t. injection. Interestingly, although both male and female mice developed mechanical hypersensitivity in response to i.t. HMGB1, female mice recovered faster. Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.

  • 2.
    Berg, L K
    et al.
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway.
    Larsson, M
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Morland, C
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway.
    Gundersen, V
    Department of Anatomy, Institute of Basic Medical Sciences, Centre for Molecular, Biology and Neuroscience (CMBN), University of Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Pre- and postsynaptic localization of NMDA receptor subunits at hippocampal mossy fibre synapses.2013Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 230, s. 139-150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The N-methyl-D-aspartate (NMDA) type of glutamate receptors is involved in synaptic plasticity in hippocampal mossy fibre-CA3 pyramidal neuron synapses. The ultrastructural localization of NMDA receptor subunits at this synapse type is not known. By postembedding electron microscopic immunogold cytochemistry we show that the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses. In the mossy fibres the GluN1, GluN2B and GluN2D labelling patterns suggested that these subunits were located also presynaptically in nerve terminal membranes and in mossy fibre axons. GluN3B was predominantly present in mossy fibre synapses as compared to recurrent associational commissural synapses, showing a presynaptic labelling pattern. In conclusion, while the postsynaptic localization of GluN1, GluN2A, GluN2B, and GluN2D is in good agreement with the recent finding of NMDA receptor-dependent long term potentiation (LTP) at CA3 mossy fibre synapses, we propose that presynaptic GluN1, GluN2B, GluN2D and GluN3B subunits could be involved in plastic phenomena such as certain types of LTP and recurrent mossy fibre growth.

  • 3.
    Bergersen, L H
    et al.
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Morland, C
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Ormel, L
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Rinholm, J E
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Larsson, Max
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Wold, J F H
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Røe, A T
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Stranna, A
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Santello, M
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Bouvier, D
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Ottersen, O P
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Volterra, A
    Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, Lausanne, Switzerland.
    Gundersen, V
    Department of Anatomy, Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Immunogold detection of L-glutamate and D-serine in small synaptic-like microvesicles in adult hippocampal astrocytes.2012Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, nr 7, s. 1690-1697Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glutamate and the N-methyl-D-aspartate receptor ligand D-serine are putative gliotransmitters. Here, we show by immunogold cytochemistry of the adult hippocampus that glutamate and D-serine accumulate in synaptic-like microvesicles (SLMVs) in the perisynaptic processes of astrocytes. The estimated concentration of fixed glutamate in the astrocytic SLMVs is comparable to that in synaptic vesicles of excitatory nerve terminals (≈ 45 and ≈ 55 mM, respectively), whereas the D-serine level is about 6 mM. The vesicles are organized in small spaced clusters located near the astrocytic plasma membrane. Endoplasmic reticulum is regularly found in close vicinity to SLMVs, suggesting that astrocytes contain functional nanodomains, where a local Ca(2+) increase can trigger release of glutamate and/or D-serine.

  • 4.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Design and Outcome of a CDIO Syllabus Survey for a Biomedicine Program2019Inngår i: The 15th International CDIO Conference: Proceedings – Full Papers / [ed] Jens Bennedsen, Aage Birkkjær Lauritsen, Kristina Edström, Natha Kuptasthien, Janne Roslöf & Robert Songer, Aarhus: Aarhus University , 2019, s. 191-200Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The CDIO Syllabus survey has successfully been applied to the Bachelor’s and Master’s programs in Experimental and Medical Biosciences, within the Faculty of Medicine and Health Sciences at Linköping University, Sweden. The programs are and have been, subject to considerable redesign with strong influence from the CDIO framework. One of the main drivers for the redesign is a shift concerning the main job market after graduation, from an academic career to industry and healthcare. One of the steps in the development process has been to carry out a Syllabus survey based on an adapted version of the CDIO Syllabus. The survey was sent out to students and to various categories of professionals, and in total 87 responses were received. The adapted version of the Syllabus and the design, execution, and outcome of the survey is presented.

  • 5.
    Kanno, Takahiro
    et al.
    Department of Physiology, Hirosaki University School of Medicine, Hirosaki, Japan.
    Ma, Xiasong
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Barg, Sebastian
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Eliasson, Lena
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Galvanovskis, Juris
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Göpel, Sven
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Larsson, Max
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Renström, Erik
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Rorsman, Patrik
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by capacitance measurements.2004Inngår i: Methods, ISSN 1046-2023, E-ISSN 1095-9130, Vol. 33, nr 4, s. 302-311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This article discusses the currently used methodologies for monitoring exocytosis as changes in cell capacitance. Details are given on composition of solutions, experimental protocols, and how the observed responses can be interpreted physiologically. The concepts are illustrated by examples from our own work on insulin-releasing pancreatic beta-cells. Finally, we consider the feasibility of applying capacitance measurements to endocrine cells in intact pancreatic islets, where the cells are electrically coupled to each other.

  • 6.
    Larsson, Max
    Department of Anatomy and Centre for Molecular Biology and NeuroscienceUniversity of Oslo, Oslo, Norway.
    Ionotropic glutamate receptors in spinal nociceptive processing.2009Inngår i: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 40, nr 3, s. 260-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glutamate is the predominant excitatory transmitter used by primary afferent synapses and intrinsic neurons in the spinal cord dorsal horn. Accordingly, ionotropic glutamate receptors mediate basal spinal transmission of sensory, including nociceptive, information that is relayed to supraspinal centers. However, it has become gradually more evident that these receptors are also crucially involved in short- and long-term plasticity of spinal nociceptive transmission, and that such plasticity have an important role in the pain hypersensitivity that may result from tissue or nerve injury. This review will cover recent findings on pre- and postsynaptic regulation of synaptic function by ionotropic glutamate receptors in the dorsal horn and how such mechanisms contribute to acute and chronic pain.

  • 7.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Non-canonical heterogeneous cellular distribution and co-localization of CaMKIIα and CaMKIIβ in the spinal superficial dorsal horn.2018Inngår i: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 223, nr 3, s. 1437-1457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key enzyme in long-term plasticity in many neurons, including in the nociceptive circuitry of the spinal dorsal horn. However, although the role of CaMKII heterooligomers in neuronal plasticity is isoform-dependent, the distribution and co-localization of CaMKII isoforms in the dorsal horn have not been comprehensively investigated. Here, quantitative immunofluorescence analysis was used to examine the distribution of the two major neuronal CaMKII isoforms, α and β, in laminae I–III of the rat dorsal horn, with reference to inhibitory interneurons and neuronal populations defined by expression of parvalbumin, calretinin, and calbindin D28k. Unexpectedly, all or nearly all inhibitory and excitatory neurons showed both CaMKIIα and CaMKIIβ immunoreactivity, although at highly variable levels. Lamina III neurons showed less CaMKIIα immunoreactivity than laminae I–II neurons. Whereas CaMKIIα immunoreactivity was found at nearly similar levels in inhibitory and excitatory neurons, CaMKIIβ generally showed considerably lower immunoreactivity in inhibitory neurons. Distinct populations of inhibitory calretinin neurons and excitatory parvalbumin neurons exhibited high CaMKIIα-to-CaMKIIβ immunoreactivity ratios. CaMKIIα and CaMKIIβ immunoreactivity showed positive correlation at GluA2+ puncta in pepsin-treated tissue. These results suggest that, unlike the forebrain, the dorsal horn is characterized by similar expression of CaMKIIα in excitatory and inhibitory neurons, whereas CaMKIIβ is less expressed in inhibitory neurons. Moreover, CaMKII isoform expression varies considerably within and between neuronal populations defined by laminar location, calcium-binding protein expression, and transmitter phenotype, suggesting differences in CaMKII function both between and within neuronal populations in the superficial dorsal horn.

  • 8.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Pax2 is persistently expressed by GABAergic neurons throughout the adult rat dorsal horn.2017Inngår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 638, s. 96-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transcription factor Pax2 is required for the differentiation of GABAergic neurons in the mouse dorsal horn. Pax2 continues to be expressed in the adult murine spinal cord and has been used as a presumed marker of GABAergic neurons in the superficial dorsal horn of the adult mouse, although a strict association between adult Pax2 expression and presence of GABA throughout the dorsal horn has not been firmly established. Moreover, whether Pax2 is selectively expressed in GABAergic dorsal horn neurons also in the rat is unknown. Here, immunofluorescent labeling of Pax2 and GABA in the lumbar spinal cord of adult rats was used to investigate this issue. Indeed, essentially all GABA immunoreactive neurons in laminae I-V were immunolabeled for Pax2. Conversely, essentially all Pax2 immunopositive neurons in these laminae exhibited somatic GABA immunolabeling. These results indicate persistent Pax2 expression in GABAergic neurons in the adult rat dorsal horn, supporting the hypothesis that Pax2 may be required for the maintenance of a GABAergic phenotype in mature inhibitory dorsal horn neurons in the rat. Furthermore, Pax2 may be used as a selective and specific general somatic marker of such neurons.

  • 9.
    Larsson, Max
    et al.
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Agalave, N
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Watanabe, M
    Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan.
    Svensson, C I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Distribution of transmembrane AMPA receptor regulatory protein (TARP) isoforms in the rat spinal cord.2013Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 248, s. 180-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) are a family of auxiliary AMPA receptor subunits that differentially modulate trafficking and many functional properties of the receptor. To investigate which TARP isoforms may be involved in AMPA receptor-mediated spinal synaptic transmission, we have mapped the localization of five of the known TARP isoforms, namely γ-2 (also known as stargazin), γ-3, γ-4, γ-7 and γ-8, in the rat spinal cord. Immunoblotting showed expression of all isoforms in the spinal cord to varying degrees. At the light microscopic level, immunoperoxidase labeling of γ-4, γ-7 and γ-8 was found throughout spinal gray matter. In white matter, γ-4 and γ-7 immunolabeling was observed in astrocytic processes and in mature oligodendrocytes. In pepsin-treated spinal cord, γ-7 often colocalized with GluA2 immunopositive puncta in the deep dorsal horn as well as in the ventral horn, but not in the superficial dorsal horn. Postembedding immunogold labeling was further used to assess the synaptic localization of γ-2, γ-7 and γ-8 in the dorsal horn. Synaptic immunogold labeling of γ-2 was sparse throughout the dorsal horn, with some primary afferent synapses weakly labeled, whereas relatively strong γ-7 immunogold labeling was found at deep dorsal horn synapses, including at synapses formed by low-threshold mechanosensitive primary afferent terminals. Prominent immunogold labeling of γ-8 was frequently detected at synapses established by primary afferent fibers. The spinal localization patterns of TARP isoforms reported here suggest that AMPA receptors at spinal synaptic populations and in glial cells may exhibit different functional characteristics owing to differences in auxiliary subunit composition.

  • 10.
    Larsson, Max
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bergersen, Linda Hildegard
    Department of Oral Biology, University of Oslo, Norway.
    Gundersen, Vidar
    Department of Anatomy, Institute for Basic Medical Sciences, University of Oslo, Norway.
    Immunogold electron microscopic quantification of small molecular compounds and proteins at synapses and other neural profiles2015Inngår i: Immunocytochemistry and related techniques: Part IV / [ed] Adalberto Merighi and Laura Lossi, Springer-Verlag New York, 2015, s. 281-297Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    This chapter describes procedures for quantifi cation of postembedding labeling at brain synapses using computer-based tools. The postembedding electron microscopic immunogold method allows detection of epitopes with a resolution of about 20–30 nm. However, plasma membranes belonging to different cells and membranes of intracellular organelles can often be located even closer together. Localizing epitopes at such membranes can reliably be performed by using computer programs, such as ImageJ, which offers automated quantifi cation of gold particles. The present chapter provides a practical description of how to use ImageJ and plug- ins to obtain an accurate representation of the subcellular localization of proteins and small molecular compounds.

  • 11.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, Lund University, Lund, Sweden.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, Lund University, Lund, Sweden.
    Different basal levels of CaMKII phosphorylated at Thr286/287 at nociceptive and low-threshold primary afferent synapses.2005Inngår i: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 21, nr 9, s. 2445-2458Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Postsynaptic autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr286/287 is crucial for the induction of long-term potentiation at many glutamatergic synapses, and has also been implicated in the persistence of synaptic potentiation. However, the availability of CaMKII phosphorylated at Thr286/287 at individual glutamatergic synapses in vivo is unclear. We used post-embedding immunogold labelling to quantitatively analyse the ultrastructural localization of CaMKII phosphorylated at Thr286/287 (pCaMKII) at synapses formed by presumed nociceptive and low-threshold mechanosensitive primary afferent nerve endings in laminae I-IV of rat spinal cord. Immunogold labelling was enriched in the postsynaptic densities of such synapses, consistent with observations in pre-embedding immunoperoxidase-stained dorsal horn. Presynaptic axoplasm also exhibited sparse immunogold labelling, in peptidergic terminals partly associated with dense core vesicles. Analysis of single or serial pCaMKII-immunolabelled sections indicated that the large majority of synapses formed either by presumed peptidergic or non-peptidergic nociceptive primary afferent terminals in laminae I-II of the spinal cord, or by presumed low-threshold mechanosensitive primary afferent terminals in laminae IIi-IV, contained pCaMKII in their postsynaptic density. However, the postsynaptic levels of pCaMKII immunolabelling at low-threshold primary afferent synapses were only approximately 50% of those at nociceptive synapses. These results suggest that constitutively autophosphorylated CaMKII in the postsynaptic density is a common characteristic of glutamatergic synapses, thus potentially contributing to maintenance of synaptic efficacy. Furthermore, pCaMKII appears to be differentially regulated between high- and low-threshold primary afferent synapses, possibly reflecting different susceptibility to synaptic plasticity between these afferent pathways.

  • 12.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Pathway-specific bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II at spinal nociceptive synapses after acute noxious stimulation.2006Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, nr 16, s. 4198-4205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An intensely painful stimulus may lead to hyperalgesia, the enhanced sensation of subsequent painful stimuli. This is commonly believed to involve facilitated transmission of sensory signals in the spinal cord, possibly by a long-term potentiation-like mechanism. However, plasticity of identified synapses in intact hyperalgesic animals has not been reported. Here, we show, using neuronal tracing and postembedding immunogold labeling, that after acute noxious stimulation (hindpaw capsaicin injections), immunolabeling of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and of CaMKII phosphorylated at Thr(286/287) (pCaMKII) are upregulated postsynaptically at synapses established by peptidergic primary afferent fibers in the superficial dorsal horn of intact rats. In contrast, postsynaptic pCaMKII immunoreactivity was instead downregulated at synapses of nonpeptidergic primary afferent C-fibers; this loss of pCaMKII immunolabel occurred selectively at distances greater than approximately 20 nm from the postsynaptic membrane and was accompanied by a smaller reduction in total CaMKII contents of these synapses. Both pCaMKII and CaMKII immunogold labeling were unaffected at synapses formed by presumed low-threshold mechanosensitive afferent fibers. Thus, distinct molecular modifications, likely indicative of plasticity of synaptic strength, are induced at different populations of presumed nociceptive primary afferent synapse by intense noxious stimulation, suggesting a complex modulation of parallel nociceptive pathways in inflammatory hyperalgesia. Furthermore, the activity-induced loss of certain postsynaptic pools of autophosphorylated CaMKII at previously unmanipulated synapses supports a role for the kinase in basal postsynaptic function.

  • 13.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Broman, Jonas
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Synaptic Plasticity and Pain: Role of Ionotropic Glutamate Receptors2011Inngår i: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 17, nr 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pain hypersensitivity that develops after tissue or nerve injury is dependent both on peripheral processes in the affected tissue and on enhanced neuronal responses in the central nervous system, including the dorsal horn of the spinal cord. It has become increasingly clear that strengthening of glutamatergic sensory synapses, such as those established in the dorsal horn by nociceptive thin-caliber primary afferent fibers, is a major contributor to sensitization of neuronal responses that leads to pain hypersensitivity. Here, the authors review recent findings on the roles of ionotropic glutamate receptors in synaptic plasticity in the dorsal horn in relation to acute and persistent pain.

  • 14.
    Larsson, Max
    et al.
    Department of Experimental Medical Science, Division of Neuroscience, Pain Research Center, Lund University, Lund, Sweden; Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Broman, Jonas
    Department of Experimental Medical Science, Division of Neuroscience, Pain Research Center, Lund University, Lund, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Translocation of GluR1-containing AMPA receptors to a spinal nociceptive synapse during acute noxious stimulation.2008Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, nr 28, s. 7084-7090Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Potentiation of spinal nociceptive transmission by synaptic delivery of AMPA receptors, via an NMDA receptor- and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway, has been proposed to underlie certain forms of hyperalgesia, the enhanced pain sensitivity that may accompany inflammation or tissue injury. However, the specific synaptic populations that may be subject to such plasticity have not been identified. Using neuronal tracing and postembedding immunogold labeling, we show that a model of acute inflammatory hyperalgesia is associated with an elevated density of GluR1-containing AMPA receptors, as well as an increased synaptic ratio of GluR1 to GluR2/3 subunits, at synapses established by C-fibers that lack the neuropeptide substance P. A more subtle increase in GluR1 immunolabeling was noted at synapses formed by substance P-containing nociceptors. No changes in either GluR1 or GluR2/3 contents were observed at synapses formed by low-threshold mechanosensitive primary afferent fibers. These results contrast with our previous observations in the same pain model of increased and decreased levels of activated CaMKII at synapses formed by peptidergic and nonpeptidergic nociceptive fibers, respectively, suggesting that the observed redistribution of AMPA receptor subunits does not depend on postsynaptic CaMKII activity. The present ultrastructural evidence of topographically specific, activity-dependent insertion of GluR1-containing AMPA receptors at a central synapse suggests that potentiation of nonpeptidergic C-fiber synapses by this mechanism contributes to inflammatory pain.

  • 15.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Morland, Cecilie
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Poblete-Naredo, Irais
    Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F., Mexico.
    Biber, Jürg
    Institute of Physiology, University Zürich, Zürich, Switzerland.
    Danbolt, Niels Christian
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Gundersen, Vidar
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
    The sodium-dependent inorganic phosphate transporter SLC34A1 (NaPi-IIa) is not localized in the mouse brain: a case of tissue-specific antigenic cross-reactivity.2011Inngår i: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 59, nr 9, s. 807-812Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The sodium-dependent inorganic phosphate transporter NaPi-IIa is expressed in the kidney. Here, the authors used a polyclonal antiserum raised against NaPi-IIa- and NaPi-IIa-deficient mice to characterize its expression in nervous tissue. Western blots showed that a NaPi-IIa immunoreactive band (~90 kDa) was only present in wild-type kidney membranes and not in kidney knockout or wild-type brain membranes. In the water-soluble fraction of wild-type and knockout brains, another band (~50 kDa) was observed; this band was not detected in the kidney. Light and electron microscopic immunohistochemistry using the NaPi-IIa antibodies showed immunolabeling of kidney tubules in wild-type but not knockout mice. In the brain, labeling of presynaptic nerve terminals was present also in NaPi-IIa-deficient mice. This labeling pattern was also produced by the NaPi-IIa preimmune serum. The authors conclude that the polyclonal antiserum is specific toward NaPi-IIa in the kidney, but in the brain, immunolabeling is caused by a cross-reaction of the antiserum with an unknown cytosolic protein that is not present in the kidney. This tissue-specific cross-reactivity highlights a potential pitfall when validating antibody specificity using knockout mouse-derived tissue other than the specific tissue of interest and underlines the utility of specificity testing using preimmune sera.

  • 16.
    Larsson, Max
    et al.
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Persson, Stefan
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Ottersen, Ole Petter
    Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Broman, Jonas
    Department of Physiological Sciences, Lund University, Lund, Sweden.
    Quantitative analysis of immunogold labeling indicates low levels and non-vesicular localization of L-aspartate in rat primary afferent terminals.2001Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 430, nr 2, s. 147-159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of L-aspartate as an excitatory neurotransmitter in primary afferent synapses in the spinal cord dorsal horn is disputed. To further investigate this issue, we examined the presence of aspartate-like immunoreactivity in primary afferent nerve terminals and other tissue components of the dorsal horn. We also examined the relationship between aspartate and glutamate immunogold labeling density and the density of synaptic vesicles in primary afferent terminals and presumed inhibitory terminals forming symmetric synapses. Weak aspartate immunosignals, similar to or lower than those displayed by presumed inhibitory terminals, were detected in both C-fiber primary afferent terminals in lamina II (dense sinusoid axon terminals, identified by morphological criteria) and in A-fiber primary afferent terminals in laminae III-IV (identified with anterograde transport of choleragenoid-horseradish peroxidase conjugate). The aspartate immunogold signal in primary afferent terminals was only about one-fourth of that in deep dorsal horn neuronal cell bodies. Further, whereas significant positive correlations were evident between synaptic vesicle density and glutamate immunogold labeling density in both A- and C-fiber primary afferent terminals, none of the examined terminal populations displayed a significant correlation between synaptic vesicle density and aspartate immunogold labeling density. Thus, our results indicate relatively low levels and a non-vesicular localization of aspartate in primary afferent terminals. It is therefore suggested that aspartate, rather than being a primary afferent neurotransmitter, serves a role in the intermediary metabolism in primary afferent terminals.

  • 17.
    Larsson, Max
    et al.
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Sawada, Keisuke
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Morland, Cecilie
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Hiasa, Miki
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Ormel, Lasse
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Moriyama, Yoshinori
    Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
    Gundersen, Vidar
    Department of Anatomy and Centre for Molecular Biology and Neuroscience, University of Oslo, N-0317 Oslo, Norway Department of Neurology, Oslo University Hospital, Norway.
    Functional and anatomical identification of a vesicular transporter mediating neuronal ATP release.2012Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, nr 5, s. 1203-1214Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ATP is known to be coreleased with glutamate at certain central synapses. However, the nature of its release is controversial. Here, we demonstrate that ATP release from cultured rat hippocampal neurons is sensitive to RNAi-mediated knockdown of the recently identified vesicular nucleotide transporter (VNUT or SLC17A9). In the intact brain, light microscopy showed particularly strong VNUT immunoreactivity in the cerebellar cortex, the olfactory bulb, and the hippocampus. Using immunoelectron microscopy, we found VNUT immunoreactivity colocalized with synaptic vesicles in excitatory and inhibitory terminals in the hippocampal formation. Moreover, VNUT immunolabeling, unlike that of the vesicular glutamate transporter VGLUT1, was enriched in preterminal axons and present in postsynaptic dendritic spines. Immunoisolation of synaptic vesicles indicated presence of VNUT in a subset of VGLUT1-containing vesicles. Thus, we conclude that VNUT mediates transport of ATP into synaptic vesicles of hippocampal neurons, thereby conferring a purinergic phenotype to these cells.

  • 18. Lindström, Sarah H
    et al.
    Sundberg, Sofie C
    Larsson, Max
    Andersson, Fredrik K
    Broman, Jonas
    Granseth, Björn
    Linköpings universitet.
    VGluT1 Deficiency Impairs Visual Attention and Reduces the Dynamic Range of Short-Term Plasticity at Corticothalamic Synapses.2019Inngår i: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, artikkel-id bhz204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The most common excitatory neurotransmitter in the central nervous system, glutamate, is loaded into synaptic vesicles by vesicular glutamate transporters (VGluTs). The primary isoforms, VGluT1 and 2, are expressed in complementary patterns throughout the brain and correlate with short-term synaptic plasticity. VGluT1 deficiency is observed in certain neurological disorders, and hemizygous (VGluT1+/-) mice display increased anxiety and depression, altered sensorimotor gating, and impairments in learning and memory. The synaptic mechanisms underlying these behavioral deficits are unknown. Here, we show that VGluT1+/- mice had decreased visual processing speeds during a sustained visual-spatial attention task. Furthermore, in vitro recordings of corticothalamic (CT) synapses revealed dramatic reductions in short-term facilitation, increased initial release probability, and earlier synaptic depression in VGluT1+/- mice. Our electron microscopy results show that VGluT1 concentration is reduced at CT synapses of hemizygous mice, but other features (such as vesicle number and active zone size) are unchanged. We conclude that VGluT1-haploinsuficiency decreases the dynamic range of gain modulation provided by CT feedback to the thalamus, and this deficiency contributes to the observed attentional processing deficit. We further hypothesize that VGluT1 concentration regulates release probability by applying a "brake" to an unidentified presynaptic protein that typically acts as a positive regulator of release.

  • 19.
    Medin, T
    et al.
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Owe, S G
    Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Rinholm, J E
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Larsson, Max
    The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Sagvolden, T
    Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Storm-Mathisen, J
    The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Bergersen, L H
    The Brain and Muscle Energy Group, Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway; The Synaptic Neurochemistry Laboratory Centre for Molecular Biology and Neuroscience and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.
    Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus.2011Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 192, s. 164-171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Functional studies indicate that the dopamine D5 receptor is involved in synaptic transmission in the hippocampus. However, previous anatomical studies have detected D5 receptor labelling primarily on the soma and main dendrites of CA1 pyramidal cells and on dendritic spines in monkey but not in rats. In order to get a better understanding of putative dopamine function in the hippocampus, we quantified the D5 receptor immunoreactivity on the pyramidal cell somas and on spines and dendrites in stratum radiatum and stratum oriens in the hippocampal CA1 region of rats by quantitative immunofluorescence and immunogold electron microscopy. The quantitative immunogold results revealed a higher labelling density on dendritic spines, notably at their synaptic membranes, compared to pyramidal cell somas and dendrites. Hence, dopamine could have effects on spines as well as on somas and dendrites. The labelling density was similar on spines in stratum oriens and stratum radiatum, but the presence of labelling varied between the spines within each stratum, indicating that the effect of dopamine could be diverse between different spines.

  • 20.
    Morland, Cecilie
    et al.
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Nordengen, Kaja
    Department of Anatomy and Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway.
    Larsson, Max
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Prolo, Laura M
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Farzampour, Zoya
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Reimer, Richard J
    Department of Neurology and Neurological Sciences and Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA.
    Gundersen, Vidar
    Center for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Rikshospitalet Oslo, Oslo, Norway.
    Vesicular uptake and exocytosis of L-aspartate is independent of sialin.2013Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 3, s. 1264-1274Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mechanism of release and the role of l-aspartate as a central neurotransmitter are controversial. A vesicular release mechanism for l-aspartate has been difficult to prove, as no vesicular l-aspartate transporter was identified until it was found that sialin could transport l-aspartate and l-glutamate when reconstituted into liposomes. We sought to clarify the release mechanism of l-aspartate and the role of sialin in this process by combining l-aspartate uptake studies in isolated synaptic vesicles with immunocyotchemical investigations of hippocampal slices. We found that radiolabeled l-aspartate was taken up into synaptic vesicles. The vesicular l-aspartate uptake, relative to the l-glutamate uptake, was twice as high in the hippocampus as in the whole brain, the striatum, and the entorhinal and frontal cortices and was not inhibited by l-glutamate. We further show that sialin is not essential for exocytosis of l-aspartate, as there was no difference in ATP-dependent l-aspartate uptake in synaptic vesicles from sialin-knockout and wild-type mice. In addition, expression of sialin in PC12 cells did not result in significant vesicle uptake of l-aspartate, and depolarization-induced depletion of l-aspartate from hippocampal nerve terminals was similar in hippocampal slices from sialin-knockout and wild-type mice. Further, there was no evidence for nonvesicular release of l-aspartate via volume-regulated anion channels or plasma membrane excitatory amino acid transporters. This suggests that l-aspartate is exocytotically released from nerve terminals after vesicular accumulation by a transporter other than sialin.

  • 21.
    Persson, Stefan
    et al.
    Department of Experimental Medical Science, Division for Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Boulland, Jean-Luc
    Institute of Basic Medical Sciences and Centre for Molecular Biology and Neuroscience, University of Oslo, Blindern, Oslo, Norway.
    Aspling, Marie
    Department of Experimental Medical Science, Division for Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Larsson, Max
    Department of Experimental Medical Science, Division for Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Fremeau, Robert T
    Departments of Neurology and Physiology, Graduate Programs in Neuroscience and Cell Biology, University of California San Francisco School of Medicine, San Francisco, California, USA.
    Edwards, Robert H
    Departments of Neurology and Physiology, Graduate Programs in Neuroscience and Cell Biology, University of California San Francisco School of Medicine, San Francisco, California, USA.
    Storm-Mathisen, Jon
    Institute of Basic Medical Sciences and Centre for Molecular Biology and Neuroscience, University of Oslo, Blindern, Oslo, Norway.
    Chaudhry, Farrukh A
    Institute of Basic Medical Sciences and Centre for Molecular Biology and Neuroscience, University of Oslo, Blindern, Oslo, Norway.
    Broman, Jonas
    Department of Experimental Medical Science, Division for Neuroscience, and Lund University Pain Research Center, Lund University, Lund, Sweden.
    Distribution of vesicular glutamate transporters 1 and 2 in the rat spinal cord, with a note on the spinocervical tract.2006Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 497, nr 5, s. 683-701Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To evaluate whether the organization of glutamatergic fibers systems in the lumbar cord is also evident at other spinal levels, we examined the immunocytochemical distribution of vesicle glutamate transporters 1 and 2 (VGLUT1, VGLUT2) at several different levels of the rat spinal cord. We also examined the expression of VGLUTs in an ascending sensory pathway, the spinocervical tract, and colocalization of VGLUT1 and VGLUT2. Mainly small VGLUT2-immunoreactive varicosities occurred at relatively high densities in most areas, with the highest density in laminae I-II. VGLUT1 immunolabeling, including small and medium-sized to large varicosities, was more differentiated, with the highest density in the deep dorsal horn and in certain nuclei such as the internal basilar nucleus, the central cervical nucleus, and the column of Clarke. Lamina I and IIo displayed a moderate density of small VGLUT1 varicosities at all spinal levels, although in the spinal enlargements a uniform density of such varicosities was evident throughout laminae I-II in the medial half of the dorsal horn. Corticospinal tract axons displayed VGLUT1, indicating that the corticospinal tract is an important source of small VGLUT1 varicosities. VGLUT1 and VGLUT2 were cocontained in small numbers of varicosities in laminae III-IV and IX. Anterogradely labeled spinocervical tract terminals in the lateral cervical nucleus were VGLUT2 immunoreactive. In conclusion, the principal distribution patterns of VGLUT1 and VGLUT2 are essentially similar throughout the rostrocaudal extension of the spinal cord. The mediolateral differences in VGLUT1 distribution in laminae I-II suggest dual origins of VGLUT1-immunoreactive varicosities in this region.

  • 22.
    Sardar Sinha, Maitrayee
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Ansell - Schultz, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Civitelli, Livia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Hildesjö, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lannfelt, Lars
    Uppsala Univ, Sweden; BioArctic AB, Sweden.
    Ingelsson, Martin
    Uppsala Univ, Sweden.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Alzheimers disease pathology propagation by exosomes containing toxic amyloid-beta oligomers2018Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, nr 1, s. 41-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The gradual deterioration of cognitive functions in Alzheimers disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimers disease and that they could serve as targets for development of new diagnostic and therapeutic principles.

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