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  • 1.
    Delsing, Louise
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden / Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Dönnes, Pierre
    SciCross AB, Skövde, Sweden.
    Sánchez, José
    Biostatistics, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Voulgaris, Dmitrios
    Department of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm.
    Herland, Anna
    Department of Micro and Nanosystems, KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden / iClinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier2018In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 36, no 12, p. 1816-1827Article in journal (Refereed)
    Abstract [en]

    Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of inter-species differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in co-culture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our co-culture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in co-culture, including upregulation of tight junction proteins such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF and PI3K-Akt pathways upon co-culture. Our data suggests that co-culture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in co-culture can be used to further improve iPSC-derived BBB models through selective pathway manipulation.

  • 2.
    Delsing, Louise
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Hicks, Ryan
    IMED Discovery Sciences, AstraZeneca, Mölndal, Sweden.
    Zetterberg, Henrik
    University of Gothenburg, Gothenburg, Sweden.
    Human iPSC-derived endothelial cells can develop in to brain-like endothelial cells after coculture with primary human brain cells2017Conference paper (Refereed)
  • 3.
    Fabre, Kristin M.
    et al.
    Microphysiological Systems Center of Excellence, Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Waltham, MA, United States.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Colclough, Nicola
    Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Crowther, Damian C.
    Neuroscience, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Ewart, Lorna
    Microphysiological Systems Center of Excellence, Drug Safety & Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
    Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting2019In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 140, p. 129-135Article in journal (Refereed)
    Abstract [en]

    Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics. © 2018

  • 4.
    Kristensson, Lisbeth
    et al.
    AstraZeneca, Mölndal, Sweden.
    Lundin, Anders
    AstraZeneca, Mölndal, Sweden / Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, David
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fryklund, Jan
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Fex, Tomas
    Emeriti Bio, AZ Bioventure Hub, Mölndal, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. AstraZeneca, Mölndal, Sweden / the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Ryberg, Erik
    AstraZeneca, Mölndal, Sweden.
    Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons2018In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 681, p. 37-43, article id S0304-3940(18)30351-3Article in journal (Refereed)
    Abstract [en]

    Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 ± 0.18 μM), glycine (EC50 11.0 ± 3.7 μM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter-screening of lead series compounds towards unwanted GABAAreceptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist.

  • 5.
    Lundin, Anders
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden / Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Clausen, Maryam
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ricchiuto, Piero
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sanchez, José
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Sabirsh, Alan
    Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Ding, Mei
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK / UK Dementia Research Institute at UCL, London, UK.
    Brolén, Gabriella
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Herland, Anna
    Department of Micro and Nanosystems KTH Royal Institute of Technology, Stockholm, Sweden / Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Falk, Anna
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models2018In: Stem Cell Reports, ISSN 2213-6711, Vol. 10, no 3, p. 1030-1045Article in journal (Refereed)
    Abstract [en]

    In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.

  • 6.
    Skillbäck, Tobias
    et al.
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Delsing, Louise
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Mattsson, Niklas
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Janelidze, Shorena
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Nägga, Katarina
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Kilander, Lena
    Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
    Hicks, Ryan
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden.
    Wimo, Anders
    Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden / Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Winblad, Bengt
    Division for Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden / Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden.
    Hansson, Oskar
    Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden / Department of Neurology, Skåne University Hospital, Lund, Sweden.
    Blennow, Kaj
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Eriksdotter, Maria
    Department Geriatric Medicine, Karolinska University Hospital, Huddinge, Sweden / Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences, and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
    Zetterberg, Henrik
    Department of Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden / Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden / Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom / UK Dementia Research Institute at UCL, London, United Kingdom.
    CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 59, p. 1-9Article in journal (Refereed)
    Abstract [en]

    A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.

  • 7.
    Wobst, Heike J.
    et al.
    AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States.
    Delsing, Louise
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, MA, United States of America / AstraZeneca, Discovery Science, Innovative Medicines and Early Development Biotech Unit, Mölndal, Sweden.
    Brandon, Nicholas J.
    AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States / AstraZeneca, Neuroscience, Innovative Medicines and Early Development, Waltham, United States.
    Moss, Stephen J.
    AstraZeneca, Tufts Laboratory for Basic and Translational Neuroscience, Tufts University, Boston, United States / Department of Neuroscience, Tufts University, School of Medicine, Boston, MA, United States.
    Truncation of the TAR DNA-binding protein 43 is not a prerequisite for cytoplasmic relocalization, and is suppressed by caspase inhibition and by introduction of the A90V sequence variant2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177181Article in journal (Refereed)
    Abstract [en]

    The RNA-binding and -processing protein TAR DNA-binding protein 43 (TDP-43) is heavily linked to the underlying causes and pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In these diseases, TDP-43 is mislocalized, hyperphosphorylated, ubiquitinated, aggregated and cleaved. The importance of TDP-43 cleavage in the disease pathogenesis is still poorly understood. Here we detail the use of D-sorbitol as an exogenous stressor that causes TDP-43 cleavage in HeLa cells, resulting in a 35 kDa truncated product that accumulates in the cytoplasm within one hour of treatment. We confirm that the formation of this 35 kDa cleavage product is mediated by the activation of caspases. Inhibition of caspases blocks the cleavage of TDP-43, but does not prevent the accumulation of full-length protein in the cytoplasm. Using D-sorbitol as a stressor and caspase activator, we also demonstrate that the A90V variant of TDP-43, which lies adjacent to the caspase cleavage site within the nuclear localization sequence of TDP-43, confers partial resistance against caspase-mediated generation of the 35 kDa cleavage product.

  • 8.
    Wobst, Heike J.
    et al.
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, United States.
    Wesolowski, Steven S.
    IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge, United States.
    Chadchankar, Jayashree
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, United States.
    Delsing, Louise
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA / IMED Biotech Unit, AstraZeneca Discovery Science, Mölndal, Sweden.
    Jacobsen, Steven
    IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge, United States.
    Mukherjee, Jayanta
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, United States.
    Deeb, Tarek Z.
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, United States.
    Dunlop, John
    IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge, United States.
    Brandon, Nicholas J.
    IMED Biotech Unit, AstraZeneca Neuroscience IMED, AstraZeneca, Cambridge, United States.
    Moss, Stephen J.
    AstraZeneca-Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, United States / Department of Neuroscience, Tufts University School of Medicine, Boston, United States.
    Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALS In vitro2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 46Article in journal (Refereed)
    Abstract [en]

    Mutations in the gene TARDBP, which encodes TAR DNA-binding protein 43 (TDP-43), are a rare cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the majority of mutations are found in the C-terminal glycine-rich domain, an alanine to valine amino acid change at position 90 (A90V) in the bipartite nuclear localization signal (NLS) of TDP-43 has been described. This sequence variant has previously been shown to cause cytoplasmic mislocalization of TDP-43 and decrease protein solubility, leading to the formation of insoluble aggregates. Since the A90V mutation has been described both in patients as well as healthy controls, its pathogenic potential in ALS and FTD remains unclear. Here we compare properties of overexpressed A90V to the highly pathogenic M337V mutation. Though both mutations drive mislocalization of the protein to the cytoplasm to the same extent, M337V produces more significant damage in terms of protein solubility, levels of pathogenic phosphorylation, and formation of C-terminal truncated protein species. Furthermore, the M337V, but not the A90V mutant, leads to a downregulation of histone deacetylase 6 and Ras GTPase-activating protein-binding protein. We conclude that in the absence of another genetic or environmental 'hit' the A90V variant is not sufficient to cause the deleterious phenotypes associated with ALS and FTD, despite prominent cytoplasmic protein relocalization of TDP-43.

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