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  • 1.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 15, p. 2458-2468Article in journal (Refereed)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 2.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Benedikz, Eirikur
    Department of Neurobiology, Division of Neurodegeneration, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 2, p. 343-358Article in journal (Refereed)
    Abstract [en]

    The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

  • 3.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland, Department of Geriatrics.
    Lindström, Tobias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1069-1082Article in journal (Refereed)
    Abstract [en]

    Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

  • 4.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Geriatric Medicine in Norrköping.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Domert, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease2014In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

  • 5.
    Amandusson, Åsa
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Hermanson, Ola
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Estrogen-induced alterations of spinal cord enkephalin gene expression1999In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 83, no 2, p. 243-248Article in journal (Refereed)
    Abstract [en]

    Enkephalin-synthesizing neurons in the super®cial laminae of the spinal and trigeminal dorsal horn are critical components of the endogenous pain-modulatory system. We have previously demonstrated that these neurons display intracellular estrogen receptors, suggesting that estrogen can potentially influence their enkephalin expression. By using Northern blot, we now show that a bolus injection of estrogen results in a rapid increase in spinal cord enkephalin mRNA levels in ovariectomized female rats. Thus, 4 h after estrogen administration the enkephalin mRNA-expression in the lumbar spinal cord was on average 68% higher (P , 0:05) than in control animals injected with vehicle only. A small increase in the amount of enkephalin mRNA was also seen after 8 h (P , 0:05), whereas no difference between estrogen-injected and control animals was found after 24 h or at time periods shorter than 4 h. Taken together with the previous anatomical data, the present findings imply that estrogen has an acute effect on spinal opioid levels in areas involved in the transmission of nociceptive information.

  • 6.
    Andin, Josefine
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Hallbeck, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Mohammed, Abdul H
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Influence of environmental enrichment on steady-state mRNA levels for EAAC1, AMPA1 and NMDA2A receptor subunits in rat hippocampus2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1174, no 1, p. 18-27Article in journal (Refereed)
    Abstract [en]

    Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment have been shown on neuronal structure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g., in Alzheimer's disease. Glutamatergic pathways are imperative for cognitive functions, such as memory, learning and long-term potentiation, and relies on the AMPA and NMDA glutamate receptors and the hippocampus, with its specific subregions, is an important anatomical substrate in this. The glutamate signalling is also dependent on a fine-tuned transport system, in the hippocampus primarily achieved by the glutamate transporter EAAC1. In this study we show how environmental enrichment modulates these parts of the glutamatergic system using quantitative in situ hybridisation. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly and region specifically decreased in the hippocampus. We also provide evidence for regional and hemisphere-specific upregulation of NMDA mRNA in the hippocampus after environmental enrichment. The current work also shows that AMPA mRNA of the hippocampus is not per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system of specific regions of the hippocampus and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions. © 2007.

  • 7.
    Bjartmar, Lisa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ruud, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Cytology.
    Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula2010In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, p. 24-33Article in journal (Refereed)
    Abstract [en]

    Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

  • 8.
    Bruhn, H.
    et al.
    Cty Hosp Ryhov, Sweden.
    Strandeus, M.
    Cty Hosp Ryhov, Sweden.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Lind, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Improved survival of Swedish glioblastoma patients treated according to Stupp2018In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 138, no 4, p. 332-337Article in journal (Refereed)
    Abstract [en]

    ObjectivesThe median survival in glioblastoma (GBM) patients used to be less than 1year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has been shown to prolong survival. The Stupp protocol was implemented in the county of Jonkoping in 2006. The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM. Material and MethodThis study includes all patients from the county of Jonkoping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001-2005 and 2006-2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan-Meier survival analysis were calculated and compared between the 2 cohorts. ResultsThe mean survival was 110days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006-2012 cohort and 1 patient in the 2001-2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001-2005 cohort (mean 163 vs 344days, Pamp;lt;.001) than in the 2006-2012 cohort (mean 220 vs 397days, P=.02). ConclusionSurvival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.

  • 9.
    Domert, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rao, Sahana Bhima
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance2014In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed)
    Abstract [en]

    The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

  • 10.
    Elander, Louise
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Engström, Linda
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    IL-1β and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-12007In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 292, no 1, p. R258-R267Article in journal (Refereed)
    Abstract [en]

    Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1β or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E2 by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1β, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1β induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wildtype controls. These data suggest that IL-1β and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1β and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions. Copyright © 2007 the American Physiological Society.

  • 11.
    Elander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Prostaglandin E2 receptors in IL-1β induced anorexiaManuscript (preprint) (Other academic)
    Abstract [en]

    Anorexia in response to immune challenge by Interleukin-1β (IL-1β) has been shown to be dependent on Prostaglandin E2 (PGE2) produced by the inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1). However, it is not known which of the four known PGE2 receptors EP1-4, encoded by the genes Ptger 1-4, that mediates the PGE2-induced anorexia. Here we examined food intake in mice deficient in EP1, EP2 and EP3, respectively, during normal conditions and following treatment with IL-1β. Neither of the gene deletions affected baseline food intake, and all the three genotypes displayed anorexia following IL-1β injection, similar to wild type mice. Previous work has demonstrated that the EP3 receptor is critical for the generation of fever, and that EP1 and EP3 receptors mediate inflammationinduced activation of the hypothalamic-pituitary-adrenal (HPA) axis. The present data, showing intact anorexigenic responses in EP1 and EP3 deficient mice, as well as in mice with deletion of the EP2 receptor, hence suggest that PGE2-elicited acute phase responses are mediated by distinct set or sets of PGE2-receptors.

  • 12.
    Engblom, David
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Ek, Monica
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Ericsson-Dahlstrand, Anders
    Department of Medicine, Unit of Rheumatology, The Karolinska Institute, Stockholm, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Distribution of prostaglandin EP3 and EP4 receptor mRNA in the rat parabrachial nucleus2000In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 281, no 2-3, p. 163-166Article in journal (Refereed)
    Abstract [en]

    By using in situ hybridization, the distribution of mRNA for the PGE2 receptors EP3 and EP4 was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP3 receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker–Fuse nuclei. EP4 receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP3 receptor mRNA. These findings suggest that EP3 and EP4 receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

  • 13.
    Gustafsson, Gabriel
    et al.
    Uppsala Univ, Sweden.
    Loov, Camilla
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Persson, Emma
    Uppsala Univ, Sweden.
    Lazaro, Diana F.
    Univ Med Ctr Gottingen, Germany.
    Takeda, Shuko
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Bergstrom, Joakim
    Uppsala Univ, Sweden.
    Erlandsson, Anna
    Uppsala Univ, Sweden.
    Sehlin, Dag
    Uppsala Univ, Sweden.
    Balaj, Leonora
    Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Gyorgy, Bence
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Outeiro, Tiago F.
    Univ Med Ctr Gottingen, Germany; Max Planck Inst Expt Med, Germany; Newcastle Univ, England.
    Breakefield, Xandra O.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Hyman, Bradley T.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Ingelsson, Martin
    Uppsala Univ, Sweden; Massachusetts Gen Hosp, MA 02129 USA; Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02115 USA.
    Secretion and Uptake of -Synuclein Via Extracellular Vesicles in Cultured Cells2018In: Cellular and molecular neurobiology, ISSN 0272-4340, E-ISSN 1573-6830, Vol. 38, no 8, p. 1539-1550Article in journal (Refereed)
    Abstract [en]

    In Parkinsons disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular -synuclein (-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of -syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of -syn can influence the distribution and secretion of -syn in human neuroblastoma cells. Different -syn variants, including -syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted -syn, 0.1-2% was associated with vesicles. The major part of EV -syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For -syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT -syn. Moreover, such EV-associated -syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T -syn displayed an increased association with EVs. Taken together, our data suggest that -syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful -syn species and thereby contribute to the pathology in -synucleinopathies.

  • 14.
    Gustafsson, Håkan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Biomedical Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Norwegian University of Science and Technology, Norway.
    Kolbun, Natallia
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jonson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Engström, Maria
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    de Muinck, Ebo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Visualization of oxidative stress in ex vivo biopsies using electron paramagnetic resonance imaging2015In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 73, no 4, p. 1682-1691Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study was to develop an X-Band electron paramagnetic resonance imaging protocol for visualization of oxidative stress in biopsies.

    METHODS: The developed electron paramagnetic resonance imaging protocol was based on spin trapping with the cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. Computer software was developed for deconvolution and back-projection of the EPR image. A phantom containing radicals of known spatial characteristic was used for evaluation of the developed protocol. As a demonstration of the technique electron paramagnetic resonance imaging of oxidative stress was performed in six sections of atherosclerotic plaques. Histopathological analyses were performed on adjoining sections.

    RESULTS: The developed computer software for deconvolution and back-projection of the EPR images could accurately reproduce the shape of a phantom of known spatial distribution of radicals. The developed protocol could successfully be used to image oxidative stress in six sections of the three ex vivo atherosclerotic plaques.

    CONCLUSIONS: We have shown that oxidative stress can be imaged using a combination of spin trapping with the cyclic hydroxylamine spin probe cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. A thorough and systematic evaluation on different types of biopsies must be performed in the future to validate the proposed technique. Magn Reson Med, 2014.

  • 15.
    Gustafsson, Håkan
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Norell, M.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Lindgren, Mikael
    Norwegian University of Science and Technology, Trondheim, Norway.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Zachrisson, Helene
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Fe(III) distribution varies substantially within and between atherosclerotic plaques2014In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 2, no 71, p. 885-892Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture.

    METHODS:

    Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy.

    RESULTS:

    Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01).

    CONCLUSION:

    Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

  • 16.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Fluorescence spectroscopy and optical coherence tomography for brain tumor detection2016Conference paper (Refereed)
    Abstract [en]

    Resection of brain tumor is a challenging task as the tumor does not have clear borders and the malignant types specifically have often a diffuse and infiltrative pattern of growth. Recently, neurosurgical microscopes have been modified to incorporate fluorescence modules for detection of tumor when 5-aminolevulinic acid (5-ALA) is used as a contrast. We have in combination with the fluorescence microscopes implemented and evaluated a fluorescence spectroscopy based handheld probe for detecting the 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX) in the gliomas in 50 patients intraoperatively. The results show a significantly high sensitivity for differentiating tumor from the healthy tissue and distinguished fluorescence intensity levels in the tumor cell infiltration zone around the tumor. However, knowledge on association of the quantified fluorescence signals specifically in the intermediate inflammatory zone with the infiltrative tumor cells can be complemented with volumetric tissue imaging and a higher precision histopathological analysis. In this work, a spectral domain optical coherence tomography (OCT) system with central wavelength of 1325nm has been used to image the tissue volume that the fluorescence is collected from and is evaluated against histopathological analysis for a higher precision slicing. The results show that although healthy brain has a homogenous microstructure in the OCT images, the brain tumor shows a distinguished texture in the images correlated with the PpIX fluorescence intensity and histopathology.

  • 17.
    Haj-Hosseini, Neda
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Milos, Peter
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hildesjö, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Detection of brain tumor using fluorescence and optical coherence tomography2015Conference paper (Refereed)
    Abstract [en]

    Resection of brain tumor is a challenging task as the tumor does not have clear borders and the malignant types specifically have often a diffuse and infiltrative pattern of growth. We have previously implemented and evaluated a fluorescence spectroscopy based handheld probe for detecting the 5-aminolevulinic acid induced protoporphyrin IX (PpIX) in the gliomas. To add another dimension to the brain tumor detection and volumetric analysis of the tissue that exhibits fluorescence, optical coherence tomography was investigated on tumor specimens.

    Material and Methods:

    A fluorescence microscopy and a spectroscopy system as reported previously were used for detecting the fluorescence signals [1, 2]. A total of 50 patients have been included for intraoperative assessment of the tumor borders using the fluorescence techniques. A spectral domain OCT imaging system (TELESTO II, Thorlabs, Inc., NJ, USA) with central wavelength of 1325 nm was used to study the tissue microstructure post operatively. The system has a resolution of 13 and 5.5 μm in the lateral and axial directions, respectively. Tissue specimens from three patients undergoing brain tumor surgery were studied using the OCT system.

    Results and Conclusion:

    Using fluorescence spectroscopy the tumor could be detected with a sensitivity of 0.84 which was significantly higher than that of the surgical microscope (0.30). Brain tissue appeared rather homogeneous in the OCT images however the highly malignant tissue showed a clear structural difference from the non-malignant or low malignant brain tumor tissue which could be related to the fluorescence signal intensities.

  • 18.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Stereotactic Brain Tumor Optical Biopsy2018Conference paper (Other academic)
    Abstract [en]

    To provide guidance for targeting diagnostic tumor tissue and to avoid vessel rupture during the biopsy procedure an application specific fiber optic probe was devel-oped. The setup incorporated an in-house developed fluorescence spectroscopy system for 5-aminolevulinic acid (5-ALA) induced protopophyrin IX (PpIX) for detection in the tumor, and laser Doppler flowmeter (LDF) system for measurement of blood perfusion. Fluorescence and blood flow were recorded millimeter-wise towards the pre-calculated target. In conclusion, the optical probe made real-time detection of tumor possible and has a potential for vessel detection during the biopsy procedures. Moreover, the PpIX fluorescence, autofluorescence and blood flow in the tumor could be studied at precise positions in the brain and the tumor. In the next step, further anal-ysis will be added.

  • 19.
    Haj-Hosseini, Neda
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery2015In: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, E-ISSN 1873-1597, Vol. 12, no 2, p. 209-214Article in journal (Refereed)
    Abstract [en]

    Background

    Using 5-aminolevulinic acid (ALA) as an intraoperative fluorescence contrast has been proven to improve the resection of glioblastoma and contribute to prolonged patient survival. ALA accumulates as protoporphyrin IX (PpIX) in the tumor cells and is administered in an advised dose of 20 mg/kg body weight (b.w.) for brain tumor resection using fluorescence surgical microscopes. PpIX fluorescence availability and intensities of a four folds lower ALA dose (5 mg/kg b.w.) has been investigated in glioblastomas and skin using a spectroscopy system adapted for surgical guidance.

    Methods

    A total of 30 adult patients diagnosed with high grade gliomas were included in the analysis. ALA was orally administered in doses of 5 mg/kg b.w. (n = 15) dissolved in orange juice or 20 mg/kg b.w. (n = 15) dissolved in water. A fluorescence spectroscopy system with a handheld fiber-optical probe was used for performing the quantitative fluorescence measurements.

    Results

    The binominal comparison of the diagnostic performance parameters showed no significant statistical difference (p > 0.05). The median fluorescence values in tumor were 2-3 times higher for the high ALA dose group. No PpIX was detected in the skin of the patients in the low dose group (0/4) while PpIX was detected in the skin of the majority of the patients in the high ALA dose group (13/14).

    Conclusions

    Application of 5 mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients.

  • 20.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milos, Peter
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy2018In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 9, no 5, p. 2284-2296Article in journal (Refereed)
    Abstract [en]

    A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real-time detection of tumor tissue and microvascular blood flow for tracking the vessels.

  • 21.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Olivecrona, Magnus
    Department of Neurosurgery, Umeå University.
    Hillman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Fluorescence guided spectroscopy versus fluorescence microscopy for brain tumor resection2013Conference paper (Other academic)
  • 22.
    Hallbeck, Martin
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Dynorphin mRNA-expressing neurons in the rat paraventricular hypothalamic nucleus project to the spinal cord2000In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 285, no 3, p. 161-164Article in journal (Refereed)
    Abstract [en]

    The opioid peptide dynorphin is important for the regulation of neuronal activity in the spinal cord. Because dynorphin is produced by neurons throughout the neuraxis, there are many putative sources for spinal dynorphin fibers, in addition to those originating from spinal cord neurons. Using a sensitive double-labeling technique combining in situ hybridization and tract tracing, the present study demonstrates that the paraventricular hypothalamic nucleus (PVH) of adult naı̈ve male Sprague–Dawley rats contains large numbers of dynorphin mRNA-producing cells with projections to the spinal cord. Thus, more than 40% of the spinally projecting neurons in PVH were found to express dynorphin mRNA. This novel finding suggests that the PVH is a major source of spinal dynorphin that may be of importance for the processing of pain and visceral information.

  • 23.
    Hallbeck, Martin
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Peptidergic projections from the rat paraventricular hypothalamic nucleus to the spinal cord2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The survival of the organism is dependent on keeping a balanced internal milieu in an ever-changing environment The process to achieve this balance is called homeostasis and it is accomplished by the consonant action of the endocrine system and the autonomic nervous system. Specific parts of the central nervous system (CNS) control these systems in response to various sensory inputs. One of the key sites for the coordinated action of these two homeostasis systems is the paraventricular hypothalamic nucleus (PVH). Tirrough its projections to the pituitary the PVH controls the release of different hormones. In addition, it projects heavily to brain stem and spinal cord autonomic centers. Furthermore, the PVH projects to the superficial layers of the spinal cord, where nerve fibers conveying pain and temperature modalities terminate. Thus, in addition to its motor control of the homeostasis system, the PVH may influence the processing of sensory inputs that are important for homeostatic regulation. The aim of this thesis was to investigate some aspects of the organization and function of the neuronal pathways projecting from the PVH to the spinal cord in the rat.

    Vasopressin, which is a peptide that is synthesized by PVH neurons, has been proposed to regulate several different processes in the spinal cord. However, the source of vasopressin fibers within the spinal cord has been a matter of some dispute. Thus, firstly, we investigated the distribution of neurons expressing vasopressin mRNA in the naive rat, thereby providing the first complete screening of the CNS for this neuropeptide at the mRNA level. The results confmn some earlier work, but also demonstrate several new sites of vasopressin mRNA synthesis. Some sites previously thought to produce vasopressin displayed no vasopressin mRNA. Our results show that the PVH is the only putative site of spinally-projecting vasopressin neurons in the naive rat Hence, all functions exerted by vasopressin in the spinal cord are likely to be controlled by the PVH.

    Secondly, we examined the neurochemical profile of the PVH neurons that project to the spinal cord. We show that 41% of these neurons express dynorphin mRNA, 20% express enkephalin mRNA, 38% express oxytocin mRNA, and 42% express vasopressin mRNA. This is the first time that dynorphin has been shown in PVH neurons with spinal projections, and the figures for the other peptides are substantially higher than what has been reported in previous shldies. In addition, we demonstrate that each of the spinal cord projecting subdivisions of the PVH displays distinct peptide expression patterns.

    Thirdly, we investigated the physiological effect of the PVH on nociceptive transmission in the spinal cord dorsal horn. However, with the present experimental approach we could not show a consistent effect of PVH stimulation on nociceptive neurons in the spinal dorsal horn. The varying results we achieved are ascribed to the functional heterogeneity of the PVH as revealed by our previous studies.

    The present data contribute to the nnderstanding of the complex organization of the PVH. The parcellation of peptide-expressing neurons into distinct spinal cord projecting subnuclei is likely to reflect distinct functional roles of these subnuclei, and may provide the anatomical basis for the ability of the PVH to control many different processes in the spinal cord The nnderstanding of the physiological profile of these different subnuclei will provide insight into the control of homeostasis.

    List of papers
    1. Preprovasopressin mRNA is not present in dorsal root ganglia of the rat
    Open this publication in new window or tab >>Preprovasopressin mRNA is not present in dorsal root ganglia of the rat
    1996 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 209, no 10, p. 125-128Article in journal (Refereed) Published
    Abstract [en]

    Immunohistochemical studies on colchic ine-treated rats have suggested that more than half of the neurons in dorsal root ganglia (DRG) contain vasopressin. Thus, vasopressin would be the most commonly found peptide in DRG neurons. In the present study we have reexamined the presence of vasopressin in DRG neurons, using a sensitive in situ hybridization method employing long riboprobes that will detect very small amounts of mRNA. The C3, C6, T2, T12, L2 and L5 DRG were studied. None of these ganglia contained any preprovasopressin mRNA. Yet, dense labeling for preprovasopressin mRNA was seen on simultaneously processed hypothalamic sections and a heavy preprotachykinin mRNA expression was seen in adjacent DRG sections. These findings demonstrate that vasopressin is not produced in DRG in normal rats.

    Keywords
    Vasopressin, In situ hybridization, Tachykinin, Spinal cord
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79557 (URN)10.1016/0304-3940(96)12616-1 (DOI)
    Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
    2. Distribution of preprovasopressin mRNA in the rat central nervous system
    Open this publication in new window or tab >>Distribution of preprovasopressin mRNA in the rat central nervous system
    1999 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 411, no 2, p. 181-200Article in journal (Refereed) Published
    Abstract [en]

    Vasopressin released in the central nervous system has been shown to be involved both in homeostatic mechanisms (e.g., water balance, thermoregulation, cardiovascular regulation, metabolism, and antinociception) and in higher brain functions (e.g., social recognition and communication, and learning and memory). Many nuclear groups have been proposed to synthesize vasopressin, but available data are conflicting. We have used a sensitive in situ hybridization technique to identify the distribution of the neurons that may be the origin of the vasopressin in the central nervous system of the male Sprague-Dawley rat. Vasopressin mRNA-expressing neurons were most abundant in the hypothalamus (e.g., the paraventricular, supraoptic, and suprachiasmatic nuclei) but were also seen in the medial amygdaloid nucleus, the bed nucleus of stria terminalis, and the nucleus of the horizontal diagonal band. Previously unreported vasopressinergic neurons were seen in the entorhinal and piriform cortices, the ventral lateral portion of the parabrachial nucleus, the pedunculopontine nucleus, and the rostral part of the ventral periaqueductal gray matter and the adjacent portion of the mesencephalic reticular nucleus. Vasopressin mRNA expression suggestive of neuronal labeling was seen in the pyramidal layer of the CA1–3 fields and the dentate gyrus of the hippocampus. In addition, vasopressin mRNA expression, probably representing axonal mRNA, was detected over the hypothalamopituitary tract. No or insignificant preprovasopressin mRNA expression was present in the cerebellum, locus coeruleus, subcoeruleus, or the spinal cord. These findings provide novel information on the distribution of vasopressin neurons that are important for our understanding of how vasopressin acts in the brain.

    Keywords
    paraventricular hypothalamus, entorhinal cortex, hippocampus, parabrachial nucleus, periaqueductal gray matter, axonal mRNA
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24941 (URN)10.1002/(SICI)1096-9861(19990823)411:2<181::AID-CNE2>3.0.CO;2-1 (DOI)9349 (Local ID)9349 (Archive number)9349 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Spinal cord-projecting vasopressinergic neurons in the rat paraventricular hypothalamus
    Open this publication in new window or tab >>Spinal cord-projecting vasopressinergic neurons in the rat paraventricular hypothalamus
    1999 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 411, no 2, p. 201-211Article in journal (Refereed) Published
    Abstract [en]

    The paraventricular hypothalamic nucleus (PVH) is a key structure for the maintenance of homeostasis. Homeostatic regulation includes modulation of signaling in the spinal cord. This may be exerted by neurons in the PVH with spinal projections. However, the PVH is not a homogeneous structure, but consists of anatomically and functionally distinct subdivisions. In this study, we have analyzed the distribution of spinal cord-projecting PVH neurons that express vasopressin, an important neuropeptide in autonomic regulation. Vasopressinergic neurons were identified with a radiolabeled riboprobe complementary to vasopressin mRNA combined with immunohistochemical labeling of retrogradely transported cholera toxin subunit b in spinally projecting neurons. More than 40% of the spinally projecting neurons in the PVH of naive Sprague-Dawley rats were found to express vasopressin mRNA. The lateral parvocellular subdivision and the ventral part of the medial parvocellular subdivision contained the densest distribution of spinal cord-projecting vasopressin mRNA-expressing neurons. The magnocellular subdivisions displayed large numbers of vasopressin mRNA-expressing neurons, but very few of those projected to the spinal cord. The dorsal parvocellular subdivision contained a large number of spinally projecting neurons, but very few of those expressed vasopressin mRNA. These findings show that the PVH gives rise to a major vasopressinergic projection to the spinal cord and that the spinal cord-projecting vasopressinergic neurons are parceled into anatomically distinct cell groups. This provides an anatomical basis for a selective activation of functionally different groups in the PVH as part of a behaviorally adaptive response, including modulation of autonomic activity and pain processing at the spinal level.

    Keywords
    in situ hybridization, retrograde labeling, subnuclei, parvocellular, mRNA
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24950 (URN)10.1002/(SICI)1096-9861(19990823)411:2<201::AID-CNE3>3.0.CO;2-3 (DOI)9360 (Local ID)9360 (Archive number)9360 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Dynorphin mRNA-expressing neurons in the rat paraventricular hypothalamic nucleus project to the spinal cord
    Open this publication in new window or tab >>Dynorphin mRNA-expressing neurons in the rat paraventricular hypothalamic nucleus project to the spinal cord
    2000 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 285, no 3, p. 161-164Article in journal (Refereed) Published
    Abstract [en]

    The opioid peptide dynorphin is important for the regulation of neuronal activity in the spinal cord. Because dynorphin is produced by neurons throughout the neuraxis, there are many putative sources for spinal dynorphin fibers, in addition to those originating from spinal cord neurons. Using a sensitive double-labeling technique combining in situ hybridization and tract tracing, the present study demonstrates that the paraventricular hypothalamic nucleus (PVH) of adult naı̈ve male Sprague–Dawley rats contains large numbers of dynorphin mRNA-producing cells with projections to the spinal cord. Thus, more than 40% of the spinally projecting neurons in PVH were found to express dynorphin mRNA. This novel finding suggests that the PVH is a major source of spinal dynorphin that may be of importance for the processing of pain and visceral information.

    Keywords
    Preprodynorphin, Paraventricular hypothalamic nucleus, In situ hybridization, Retrograde labeling, Parvocellular, Descending
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-25043 (URN)10.1016/S0304-3940(00)01093-4 (DOI)9469 (Local ID)9469 (Archive number)9469 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
    5. Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord
    Open this publication in new window or tab >>Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord
    2001 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 433, no 2, p. 222-238Article in journal (Refereed) Published
    Abstract [en]

    The paraventricular hypothalamic nucleus (PVH) exerts many of its regulatory functions through projections to spinal cord neurons that control autonomic and sensory functions. By using in situ hybridization histochemistry in combination with retrograde tract tracing, we analyzed the peptide expression among neurons in the rat PVH that send axons to the spinal cord. Projection neurons were labeled by immunohistochemical detection of retrogradely transported cholera toxin subunit B, and radiolabeled long riboprobes were used to identify neurons containing dynorphin, enkephalin, or oxytocin mRNA. Of the spinally projecting neurons in the PVH, approximately 40% expressed dynorphin mRNA, 40% expressed oxytocin mRNA, and 20% expressed enkephalin mRNA. Taken together with our previous findings on the distribution of vasopressin-expressing neurons in the PVH (Hallbeck and Blomqvist [1999] J. Comp. Neurol. 411:201–211), the results demonstrated that the different PVH subdivisions display distinct peptide expression patterns among the spinal cord–projecting neurons. Thus, the lateral parvocellular subdivision contained large numbers of spinal cord–projecting neurons that express any of the four investigated peptides, whereas the ventral part of the medial parvocellular subdivision displayed a strong preponderance for dynorphin- and vasopressin-expressing cells. The dorsal parvocellular subdivision almost exclusively contained dynorphin- and oxytocin-expressing spinal cord–projecting neurons. This parcellation of the peptide-expressing neurons suggested a functional diversity among the spinal cord–projecting subdivisions of the PVH that provide an anatomic basis for its various and distinct influences on autonomic and sensory processing at the spinal level.

    Keywords
    dynorphin, enkephalin, oxytocin, vasopressin, mRNA, in situ hybridization, retrograde labeling, parvocellular
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24946 (URN)10.1002/cne.1137 (DOI)9355 (Local ID)9355 (Archive number)9355 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    6. Effect of Stimulation of the Paraventricular Hypothalamic Nucleus on Noxious-Evoked Fos-immunoreactlvity In the Rat lumbar Spinal Cord
    Open this publication in new window or tab >>Effect of Stimulation of the Paraventricular Hypothalamic Nucleus on Noxious-Evoked Fos-immunoreactlvity In the Rat lumbar Spinal Cord
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The paraventricular nucleus of the hypothalamus (PVH) provides a prominent descending projection to the superficial dorsal horn, and contains a number of neuropeptides that are know to influence nociceptive processing. In the present study, we injected formalin subcutaneously into the hind paws of unanesthetized rats and studied the noxious-evoked Fos protein expression in the dorsal horn following simultaneous unilateral injection of the glutamate receptor agonist kainic acid into the PVH. Although some cases displayed less Fos-inununoreactivity in the lumbar spinal cord on the side ipsilateral to the PVH activation than on the contralateral side, others displayed no side differences, and one case showed more labeling in the ipsilateral dorsal horn than on the contralateral side, Because different parts of the PVH were activated in the different experiments, the present observations suggest that the different peptide expressing populations of spinal cordprojecting neurons in PVH may have different, and perhaps opposing functions in the spinal dorsal horn.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79560 (URN)
    Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2012-08-08Bibliographically approved
  • 24.
    Hallbeck, Martin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Effect of Stimulation of the Paraventricular Hypothalamic Nucleus on Noxious-Evoked Fos-immunoreactlvity In the Rat lumbar Spinal CordManuscript (preprint) (Other academic)
    Abstract [en]

    The paraventricular nucleus of the hypothalamus (PVH) provides a prominent descending projection to the superficial dorsal horn, and contains a number of neuropeptides that are know to influence nociceptive processing. In the present study, we injected formalin subcutaneously into the hind paws of unanesthetized rats and studied the noxious-evoked Fos protein expression in the dorsal horn following simultaneous unilateral injection of the glutamate receptor agonist kainic acid into the PVH. Although some cases displayed less Fos-inununoreactivity in the lumbar spinal cord on the side ipsilateral to the PVH activation than on the contralateral side, others displayed no side differences, and one case showed more labeling in the ipsilateral dorsal horn than on the contralateral side, Because different parts of the PVH were activated in the different experiments, the present observations suggest that the different peptide expressing populations of spinal cordprojecting neurons in PVH may have different, and perhaps opposing functions in the spinal dorsal horn.

  • 25.
    Hallbeck, Martin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Spinal cord-projecting vasopressinergic neurons in the rat paraventricular hypothalamus1999In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 411, no 2, p. 201-211Article in journal (Refereed)
    Abstract [en]

    The paraventricular hypothalamic nucleus (PVH) is a key structure for the maintenance of homeostasis. Homeostatic regulation includes modulation of signaling in the spinal cord. This may be exerted by neurons in the PVH with spinal projections. However, the PVH is not a homogeneous structure, but consists of anatomically and functionally distinct subdivisions. In this study, we have analyzed the distribution of spinal cord-projecting PVH neurons that express vasopressin, an important neuropeptide in autonomic regulation. Vasopressinergic neurons were identified with a radiolabeled riboprobe complementary to vasopressin mRNA combined with immunohistochemical labeling of retrogradely transported cholera toxin subunit b in spinally projecting neurons. More than 40% of the spinally projecting neurons in the PVH of naive Sprague-Dawley rats were found to express vasopressin mRNA. The lateral parvocellular subdivision and the ventral part of the medial parvocellular subdivision contained the densest distribution of spinal cord-projecting vasopressin mRNA-expressing neurons. The magnocellular subdivisions displayed large numbers of vasopressin mRNA-expressing neurons, but very few of those projected to the spinal cord. The dorsal parvocellular subdivision contained a large number of spinally projecting neurons, but very few of those expressed vasopressin mRNA. These findings show that the PVH gives rise to a major vasopressinergic projection to the spinal cord and that the spinal cord-projecting vasopressinergic neurons are parceled into anatomically distinct cell groups. This provides an anatomical basis for a selective activation of functionally different groups in the PVH as part of a behaviorally adaptive response, including modulation of autonomic activity and pain processing at the spinal level.

  • 26.
    Hallbeck, Martin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hermanson, Ola
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Preprovasopressin mRNA is not present in dorsal root ganglia of the rat1996In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 209, no 10, p. 125-128Article in journal (Refereed)
    Abstract [en]

    Immunohistochemical studies on colchic ine-treated rats have suggested that more than half of the neurons in dorsal root ganglia (DRG) contain vasopressin. Thus, vasopressin would be the most commonly found peptide in DRG neurons. In the present study we have reexamined the presence of vasopressin in DRG neurons, using a sensitive in situ hybridization method employing long riboprobes that will detect very small amounts of mRNA. The C3, C6, T2, T12, L2 and L5 DRG were studied. None of these ganglia contained any preprovasopressin mRNA. Yet, dense labeling for preprovasopressin mRNA was seen on simultaneously processed hypothalamic sections and a heavy preprotachykinin mRNA expression was seen in adjacent DRG sections. These findings demonstrate that vasopressin is not produced in DRG in normal rats.

  • 27.
    Hallbeck, Martin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Hermansson, Ola
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Distribution of preprovasopressin mRNA in the rat central nervous system1999In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 411, no 2, p. 181-200Article in journal (Refereed)
    Abstract [en]

    Vasopressin released in the central nervous system has been shown to be involved both in homeostatic mechanisms (e.g., water balance, thermoregulation, cardiovascular regulation, metabolism, and antinociception) and in higher brain functions (e.g., social recognition and communication, and learning and memory). Many nuclear groups have been proposed to synthesize vasopressin, but available data are conflicting. We have used a sensitive in situ hybridization technique to identify the distribution of the neurons that may be the origin of the vasopressin in the central nervous system of the male Sprague-Dawley rat. Vasopressin mRNA-expressing neurons were most abundant in the hypothalamus (e.g., the paraventricular, supraoptic, and suprachiasmatic nuclei) but were also seen in the medial amygdaloid nucleus, the bed nucleus of stria terminalis, and the nucleus of the horizontal diagonal band. Previously unreported vasopressinergic neurons were seen in the entorhinal and piriform cortices, the ventral lateral portion of the parabrachial nucleus, the pedunculopontine nucleus, and the rostral part of the ventral periaqueductal gray matter and the adjacent portion of the mesencephalic reticular nucleus. Vasopressin mRNA expression suggestive of neuronal labeling was seen in the pyramidal layer of the CA1–3 fields and the dentate gyrus of the hippocampus. In addition, vasopressin mRNA expression, probably representing axonal mRNA, was detected over the hypothalamopituitary tract. No or insignificant preprovasopressin mRNA expression was present in the cerebellum, locus coeruleus, subcoeruleus, or the spinal cord. These findings provide novel information on the distribution of vasopressin neurons that are important for our understanding of how vasopressin acts in the brain.

  • 28.
    Hallbeck, Martin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Larhammar, Dan
    Department of Neuroscience, Unit of Pharmacology, Uppsala University, Sweden.
    Blomqvist, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord2001In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 433, no 2, p. 222-238Article in journal (Refereed)
    Abstract [en]

    The paraventricular hypothalamic nucleus (PVH) exerts many of its regulatory functions through projections to spinal cord neurons that control autonomic and sensory functions. By using in situ hybridization histochemistry in combination with retrograde tract tracing, we analyzed the peptide expression among neurons in the rat PVH that send axons to the spinal cord. Projection neurons were labeled by immunohistochemical detection of retrogradely transported cholera toxin subunit B, and radiolabeled long riboprobes were used to identify neurons containing dynorphin, enkephalin, or oxytocin mRNA. Of the spinally projecting neurons in the PVH, approximately 40% expressed dynorphin mRNA, 40% expressed oxytocin mRNA, and 20% expressed enkephalin mRNA. Taken together with our previous findings on the distribution of vasopressin-expressing neurons in the PVH (Hallbeck and Blomqvist [1999] J. Comp. Neurol. 411:201–211), the results demonstrated that the different PVH subdivisions display distinct peptide expression patterns among the spinal cord–projecting neurons. Thus, the lateral parvocellular subdivision contained large numbers of spinal cord–projecting neurons that express any of the four investigated peptides, whereas the ventral part of the medial parvocellular subdivision displayed a strong preponderance for dynorphin- and vasopressin-expressing cells. The dorsal parvocellular subdivision almost exclusively contained dynorphin- and oxytocin-expressing spinal cord–projecting neurons. This parcellation of the peptide-expressing neurons suggested a functional diversity among the spinal cord–projecting subdivisions of the PVH that provide an anatomic basis for its various and distinct influences on autonomic and sensory processing at the spinal level.

  • 29.
    Hallbeck, Martin
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Neuron-to-Neuron Transmission of Neurodegenerative Pathology2013In: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 19, no 6, p. 560-566Article, review/survey (Refereed)
    Abstract [en]

    One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.

  • 30.
    Kastrup, Ylva
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Hallbeck, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Amandusson, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Hirata, S
    Hermansson, O
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Blomqvist, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Progesterone receptor expression in the brainstem of the female rat.1999In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 275, p. 85-88Article in journal (Refereed)
  • 31.
    Lilledahl, Magnus B.
    et al.
    Norwegian University of Science and Technoogy, Norway.
    Gustafsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Biomedical Engineering.
    Gunnar Ellingsen, Pal
    Norwegian University of Science and Technoogy, Norway.
    Zachrisson, Helene
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenhjem Hagen, Vegard
    Norwegian University of Science and Technoogy, Norway.
    Kildemo, Morten
    Norwegian University of Science and Technoogy, Norway.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology. Norwegian University of Science and Technoogy, Norway.
    Combined imaging of oxidative stress and microscopic structure reveals new features in human atherosclerotic plaques2015In: Journal of Biomedical Optics, ISSN 1083-3668, E-ISSN 1560-2281, Vol. 20, no 2, p. 020503-Article in journal (Refereed)
    Abstract [en]

    Human atherosclerotic samples collected by carotid endarterectomy were investigated using electronic paramagnetic resonance imaging (EPRI) for visualization of reactive oxygen species, and nonlinear optical microscopy (NLOM) to study structural features. Regions of strong EPRI signal, indicating a higher concentration of reactive oxygen species and increased inflammation, were found to colocalize with regions dense in cholesterol crystals as revealed by NLOM.

  • 32.
    Mosrati, Mohamed Ali
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Krysztofiak, Adam
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Bratthall, Charlotte
    Dist Hospital, Sweden.
    Strandeus, Michael
    Ryhov Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 18, p. 16663-16673Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

  • 33.
    Nath, Sangeeta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Roshan, Firoz
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Granseth, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 26, p. 8767-8777Article in journal (Refereed)
    Abstract [en]

    Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

  • 34.
    Nilsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Elander, Louise
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Örtegren (Kugelberg), Unn
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Blomqvist, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 60, p. 27-31Article in journal (Refereed)
    Abstract [en]

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1–4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

  • 35.
    Richter, Johan
    et al.
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Haj Hosseini, Neda
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Combination of Hand-Held Probe and Microscopy for Fluorescence Guided Surgery in the Brain Tumor Marginal Zone2017In: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, Vol. 18, p. 185-192Article in journal (Refereed)
    Abstract [en]

    Background

    Visualization of the tumor is crucial for differentiating malignant tissue from healthy brain during surgery, especially in the tumor marginal zone. The aim of the study was to introduce a fluorescence spectroscopy-based hand-held probe (HHF-probe) for tumor identification in combination with the fluorescence guided resection surgical microscope (FGR-microscope), and evaluate them in terms of diagnostic performance and practical aspects of fluorescence detection.

    Material and Methods

    Eighteen operations were performed on 16 patients with suspected high-grade glioma. The HHF-probe and the FGR-microscope were used for detection of protoporphyrin (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) and evaluated against histopathological analysis and visual grading done through the FGR-microscope by the surgeon. A ratio of PpIX fluorescence intensity to the autofluorescence intensity (fluorescence ratio) was used to quantify the spectra detected by the probe.

    Results

    Fluorescence ratio medians (range 0 – 40) measured by the probe were related to the intensity of the fluorescence in the FGR-microscope, categorized as “none” (0.3, n = 131), “weak” (1.6, n = 34) and “strong” (5.4, n = 28). Of 131 “none” points in the FGR-microscope, 88 (67%) exhibited fluorescence with the HHF-probe. For the tumor marginal zone, the area under the receiver operator characteristics (ROC) curve was 0.49 for the FGR-microscope and 0.65 for the HHF-probe.

    Conclusions

    The probe was integrated in the established routine of tumor resection using the FGR-microscope. The HHF-probe was superior to the FGR-microscope in sensitivity; it detected tumor remnants after debulking under the FGR-microscope. The combination of the HHF-probe and the FGR-microscope was beneficial especially in the tumor marginal zone.

  • 36.
    Sardar Sinha, Maitrayee
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Villamil Giraldo, Ana Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified alpha-synuclein oligomers2018In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, no 9, p. 3060-3068Article in journal (Refereed)
    Abstract [en]

    Parkinsons disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of alpha-synuclein (alpha-syn). The normal function of alpha-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. alpha-Syn localizes at synaptic terminals where it can bind to synaptic vesicles as well as to other cellular membranes. It has become clear that these interactions have an impact on both alpha-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of alpha-syn covalently modified with 4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation and has been implicated in the pathogenesis of different neurodegenerative diseases by modifying the kinetics of soluble toxic oligomers. Although HNE-modified alpha-syn has been reported to assemble into stable oligomers, we found that slightly acidic conditions promoted further protein aggregation. Lipid vesicles delayed the aggregation process in a concentration-dependent manner, an effect that was observed only when they were added at the beginning of the aggregation process. Co-aggregation of lipid vesicles with HNE-modified alpha-syn also induced cytotoxic effects on differentiated SHSY-SY cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-alpha-syn under acidic conditions in relation to protein-lipid interactions our study gives a framework to examine a possible pathway leading from a physiological setting to the pathological outcome of PD.

  • 37.
    Sjöwall, Christoffer
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Letter: Clinically suspected recurrence of gastric carcinoid proved to be hypocomplementaemic urticarial vasculitis syndrome with pulmonary involvement2015In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 4, p. 337-339Article in journal (Other academic)
    Abstract [en]

    n/a

  • 38.
    van Thuijl, Hinke F.
    et al.
    University of Calif San Francisco, CA 94143 USA; Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Mazor, Tali
    University of Calif San Francisco, CA 94143 USA.
    Johnson, Brett E.
    University of Calif San Francisco, CA 94143 USA.
    Fouse, Shaun D.
    University of Calif San Francisco, CA 94143 USA.
    Aihara, Koki
    University of Tokyo, Japan; University of Tokyo, Japan.
    Hong, Chibo
    University of Calif San Francisco, CA 94143 USA.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Heimans, Jan J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Kloezeman, Jenneke J.
    Erasmus MC, Netherlands.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lamfers, Martine L. M.
    Erasmus MC, Netherlands.
    Saito, Nobuhito
    University of Tokyo, Japan.
    Aburatani, Hiroyuki
    University of Tokyo, Japan.
    Mukasa, Akitake
    University of Tokyo, Japan.
    Berger, Mitchell S.
    University of Calif San Francisco, CA 94143 USA.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Molinaro, Annette M.
    University of Calif San Francisco, CA 94143 USA; University of Calif San Francisco, CA 94143 USA.
    Wesseling, Pieter
    Vrije University of Amsterdam Medical Centre, Netherlands; Radboud University of Nijmegen, Netherlands.
    Reijneveld, Jaap C.
    Vrije University of Amsterdam Medical Centre, Netherlands; University of Amsterdam, Netherlands.
    Chang, Susan M.
    University of Calif San Francisco, CA 94143 USA.
    Ylstra, Bauke
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Costello, Joseph F.
    University of Calif San Francisco, CA 94143 USA.
    Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, p. 597-607Article in journal (Refereed)
    Abstract [en]

    Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  • 39.
    Zheng, Lin
    et al.
    Karolinska Inst, NVS, KI Alzheimers Dis Res Ctr, S-14186 Stockholm, Sweden.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, SE-141 57, Stockholm,Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences.
    Hultenby, Kjell
    Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Terman, Alexi
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.
    Intracellular localization of amyloid beta peptide in SH-SY5Y neuroblastoma cells2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 4, p. 713-733Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta peptide (A beta), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of A beta is localized extralysosomally, while oxidative stress significantly increases intralysosomal A beta content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal A beta in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal A beta. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal conditions A beta (A beta(40), A beta(42), and A beta oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with A beta PP Swedish KM670/671NL double mutation showed enlarged amount of A beta colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic A beta as well as A beta colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased A beta localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular A beta is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or A beta overproduction increased intracellular A beta levels but did not dramatically changed its localization pattern.

  • 40.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric.
    Cedazo-Minguez, Angel
    KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, Stockholm, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jerhammar, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Terman, Alexei
    Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system.2012In: Translational Neurodegeneration, ISSN 2047-9158, Vol. 1, no 1, p. 19-Article in journal (Refereed)
    Abstract [en]

    Background

    Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.

    Methods

    Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.

    Results

    Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.

    Conclusion

    Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.

  • 41.
    Zheng, Lin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Terman, Alexi
    Karolinska University Hospital, Stockholm.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Dehvari, Nodi
    Karolinska Institutet, Stockholm.
    Cowburn, Richard F.
    AstraZeneca, Södertälje.
    Benedikz, Eirikur
    Karolinska Institutet.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Cedazo-Minguez, Angel
    Karolinska Institutet.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells2011In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 7, no 12, p. 1528-1545Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days, and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide aditional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

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