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  • 1.
    Aronsson, Göran
    et al.
    Department of Biochemistry, Umeå University.
    Brorsson, Ann-Christin
    Department of Biochemistry, Umeå University.
    Sahlman, Lena
    Department of Biochemistry, Umeå University.
    Jonsson, Bengt Harald
    Department of Biochemistry, Umeå University.
    Remarkably slow folding of a small protein.1997In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 411, no 2-3, p. 359-364Article in journal (Refereed)
    Abstract [en]

    Equilibrium denaturation of the 72 amino acid alpha/beta-protein MerP, by acid, guanidine hydrochloride, or temperature, is fully reversible and follows a two-state model in which only the native and unfolded states are populated. A cis-trans equilibrium around a proline peptide bond causes a heterogeneity of the unfolded state and gives rise to a slow- and a fast folding population. With a rate constant of 1.2 s(-1) for the major fast folding population, which has none of the common intrinsically slow steps, MerP is the slowest folding protein of this small size yet reported.

  • 2.
    Bergkvist, Liza
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Helmfors, Linda
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Co-expression of a disease-associated lysozyme variant with human lysozyme in Drosophila causes accumulation of amyloid deposits and neurodegenerationManuscript (preprint) (Other academic)
    Abstract [en]

    Lysozyme amyloidosis is a dominantly inherited form of amyloid disease. Mutant variants of the protein, with increased tendencies to aggregate compared to the wild type (WT), accumulate in large amyloid deposits in multiple organs, eventually leading to organ failure. Humans affected by lysozyme amyloidosis carry one allele for the wild type protein and one allele encoding for a mutant variant of lysozyme. We have used a Drosophila melanogaster model to investigate the effect of co-expressing WT lysozyme and a mutated variant, F57I, in the central nervous system (CNS) of the fly. In this study, using activity and longevity assays, WT-F57I flies showed a lower activity and a shorter lifespan than flies expressing only WT or the F57I variant of lysozyme (median survival 16 days compared to 34 and 23 respectively). This indicates deteriorating neurological functions in WT-F57I flies; exceeding the decrease in neurological function previously observed for flies only expressing the mutated variant, F57I. In addition, accumulation of insoluble species with amyloid structure was detected for the WT-F57I flies but not for the WT or the F57I flies. Our study show that co-expression of WT lysozyme and the amyloidogenic variant F57I results in neurological damage and is required for accumulation of amyloid deposits, which is characteristic for the disease observed in humans. Our data suggest that insoluble amyloid species or intermediate species, formed on the pathway toward amyloid species, may be cytotoxic and thus contribute to the impaired neurological functions observed for the WT-F57I flies.

  • 3.
    Berglund, Anders
    et al.
    Department of Chemistry, Umeå University.
    Brorsson, Ann-Christin
    Biochemistry, Umeå University.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Sethson, Ingmar
    Department of Chemistry, Umeå University.
    The equilibrium unfolding of MerP characterized by multivariate analysis of 2D NMR data2005In: Journal of magnetic resonance, ISSN 1090-7807, E-ISSN 1096-0856, Vol. 172, no 1, p. 24-30Article in journal (Refereed)
    Abstract [en]

    A general problem when analysing NMR spectra that reflect variations in the environment of target molecules is that different resonances are affected to various extents. Often a few resonances that display the largest frequency changes are selected as probes to reflect the examined variation, especially in the case, where the NMR spectra contain numerous resonances. Such a selection is dependent on more or less intuitive judgements and relying on the observed spectral variation being primarily caused by changes in the NMR sample. Second, recording changes observed for a few (albeit significant) resonances is inevitably accompanied by not using all available information in the analysis. Likewise, the commonly used chemical shift mapping (CSM) [Biochemistry 39 (2000) 26, Biochemistry 39 (2000) 12595] constitutes a loss of information since the total variation in the data is not retained in the projection into this single variable. Here, we describe a method for subjecting 2D NMR time-domain data to multivariate analysis and illustrate it with an analysis of multiple NMR experiments recorded at various folding conditions for the protein MerP. The calculated principal components provide an unbiased model of variations in the NMR spectra and they can consequently be processed as NMR data, and all the changes as reflected in the principal components are thereby made available for visual inspection in one single NMR spectrum. This approach is much less laborious than consideration of large numbers of individual spectra, and it greatly increases the interpretative power of the analysis. © 2004 Elsevier Inc. All rights reserved.

  • 4.
    Bolognesi, B
    et al.
    University of Cambridge, Cambridge, UK.
    Jahn, T R
    University of Cambridge, Cambridge, UK.
    Brorsson, Ann-Christin
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology.
    Luheshi, L M
    University of Cambridge, Cambridge, UK.
    Yerbury, J J
    University of Wollongong, Wollongong, NSW, Australia .
    Crowther, D C
    University of Cambridge, Cambridge, UK.
    Dobson, C M
    University of Cambridge, Cambridge, UK.
    The N-terminus of amyloid-beta plays a crucial role in its aggregation and toxicity2010In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, no Suppl. 1, p. 79-80Article in journal (Other academic)
    Abstract [en]

    The aggregation of Amyloid Beta (Aß) peptide into insolubleamyloid fibrils that deposit in the brain is one of the primarypathogenic events in Alzheimer’s disease. We have previouslyshown, using a Drosophila model of Aß toxicity, that the N terminus of the Aß peptide, despite being unstructured in themature Aß fibril, nonetheless affects Aß induced neurodegeneration in vivo. In order to understand the contribution of the N terminusof Aß to its aggregation behaviour, we have investigated anumber of rationally designed N-terminal mutants in vitro. We find that single amino acid mutations in this region affect significantlythe kinetics of Aß aggregation in vitro as measured by arange of spectroscopic techniques. Furthermore, we observe striking differences in the morphology of the aggregated speciesformed by these different Aß mutants when imaged with TEM or  AFM  and  also  in the ß-sheet  content  of their  mature  fibrils. Interestingly, mutants with an increased net charge or lower hydrophobicity tend  to show slower aggregation  kinetics, and  to form more ordered  aggregates  whereas mutations that  reduce net charge   or   increase   hydrophobicity   favour   faster   aggregation kinetics   and   poorly   structured  aggregates.   In   addition,    the exposed  hydrophobicity of aggregates  formed  in the early stages of aggregation  is correlated  to their toxicity.  These findings demonstrate  not  only that  the N-terminus of the Aß peptide  plays a crucial  role  in its aggregation  and  toxicity  but  also  suggest that this  region  of Aß  may  modulate  in vivo toxicity  by altering  the conformations of aggregates that  it forms.

  • 5.
    Brorsson, Ann-Christin
    et al.
    University of Cambridge.
    Bolognesi, Benedetta
    University of Cambridge.
    Tartaglia, Gian Gaetano
    University of Cambridge.
    Shammas, Sarah L
    University of Cambridge.
    Favrin, Giorgio
    University of Cambridge.
    Watson, Ian
    University of Cambridge.
    Lomas, David A
    University of Cambridge.
    Chiti, Fabrizio
    Università degli Studi di Firenze, Italy.
    Vendruscolo, Michele
    University of Cambridge.
    Dobson, Christopher M
    University of Cambridge.
    Crowther, Damian C
    University of Cambridge.
    Luheshi, Leila M
    University of Cambridge.
    Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 8, p. 1677-84Article in journal (Refereed)
    Abstract [en]

    The extent to which proteins aggregate into distinct structures ranging from prefibrillar oligomers to amyloid fibrils is key to the pathogenesis of many age-related degenerative diseases. We describe here for the Alzheimer's disease-related amyloid beta peptide (Abeta) an investigation of the sequence-based determinants of the balance between the formation of prefibrillar aggregates and amyloid fibrils. We show that by introducing single-point mutations, it is possible to convert the normally harmless Abeta40 peptide into a pathogenic species by increasing its relative propensity to form prefibrillar but not fibrillar aggregates, and, conversely, to abolish the pathogenicity of the highly neurotoxic E22G Abeta42 peptide by reducing its relative propensity to form prefibrillar species rather than mature fibrillar ones. This observation can be rationalized by the demonstration that whereas regions of the sequence of high aggregation propensity dominate the overall tendency to aggregate, regions with low intrinsic aggregation propensities exert significant control over the balance of the prefibrillar and fibrillar species formed, and therefore play a major role in determining the neurotoxicity of the Abeta peptide.

  • 6.
    Brorsson, Ann-Christin
    et al.
    Department of Biochemistry, Umeå University.
    Kjellson, Annika
    Department of Biochemistry, Umeå University.
    Aronsson, Göran
    Biopool AB.
    Sethson, Ingmar
    Department of Organic Chemistry, Umeå University.
    Hambraeus, Charlotta
    University of Southern Stockholm.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    The "two-state folder" MerP forms partially unfolded structures that show temperature dependent hydrogen exchange2004In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 340, no 2, p. 333-344Article in journal (Refereed)
    Abstract [en]

    We have analysed the folding energy landscape of the 72 amino acid protein MerP by monitoring native state hydrogen exchange as a function of temperature in the range of 7-55°C. The temperature dependence of the hydrogen exchange has allowed us to determine ΔG, ΔH and ΔCp values for the conformational processes that permit hydrogen exchange. When studied with the traditional probes, fluorescence and CD, MerP appears to behave as a typical two-state protein, but the results from the hydrogen exchange analysis reveal a much more complex energy landscape. Analysis at the individual amino acid level show that exchange is allowed from an ensemble of partially unfolded structures (i.e. intermediates) in which the stabilities at the amino acid level form a broad distribution throughout the protein. The formation of partially unfolded structures might contribute to the unusually slow folding of MerP. © 2004 Elsevier Ltd. All rights reserved.

  • 7.
    Brorsson, Ann-Christin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Kumita, Janet R.
    University of Cambridge.
    MacLeod, Ian
    University of Cambridge.
    Bolognesi, Benedetta
    University of Cambridge.
    Speretta, Elena
    University of Cambridge.
    Luheshi, Leila M.
    University of Cambridge.
    Knowles, Tuomas P.
    University of Cambridge.
    Dobson, Christopher M.
    University of Cambridge.
    Crowther, Damian C.
    University of Cambridge.
    Methods and models in neurodegenerative and systemic protein aggregation diseases2010In: Frontiers in bioscience : a journal and virtual library, ISSN 1093-4715, Vol. 15, p. 373-396Article, review/survey (Refereed)
    Abstract [en]

    Protein misfolding and aggregation are implicated in a wide range of increasingly prevalent human diseases ranging from dementia to diabetes. In this review we discuss the current experimental strategies that are being employed in the investigation of the pathogenesis of three important protein misfolding disorders. The first, Alzheimers disease (AD), is the most prevalent neurodegenerative disease and is thought to be initiated by the aggregation of a natively unstructured peptide called amyloid beta (Abeta). We discuss methods for the characterization of the aggregation properties of Abeta in vitro and how the results of such experiments can be correlated with data from animal models of disease. We then consider another form of amyloidosis, where a systemic distribution of amyloid deposit is caused by aggregation and deposition of mutational variants of lysozyme. We describe how experiments in vitro, and more recently in vivo, have provided insights into the origins of this disease. Finally we outline the varied paradigms that have been employed in the study of the serpinopathies, and in particular, a dementia caused by neuroserpin polymerization.

  • 8.
    Brorsson, Ann-Christin
    et al.
    Department of Biochemistry, Umeå University.
    Lundqvist, Martin
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Sethson, Ingmar
    Department of Organic Chemistry Umeå University.
    Jonsson, Bengt-Harald
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    GuHCl and NaCl-dependent hydrogen exchange in MerP reveals a well-defined core with an unusual exchange pattern2006In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 357, no 5, p. 1634-1646Article in journal (Refereed)
    Abstract [en]

    We have analysed hydrogen exchange at amide groups to characterise the energy landscape of the 72 amino acid residue protein MerP. From the guanidine hydrochloride (GuHCl) dependence of exchange in the pre-transitional region we have determined free energy values of exchange (ΔGHX) and corresponding m-values for individual amide protons. Detailed analysis of the exchange patterns indicates that for one set of amide protons there is a weak dependence on denaturant, indicating that the exchange is dominated by local fluctuations. For another set of amide protons a linear, but much stronger, denaturant dependence is observed. Notably, the plots of free energy of exchange versus [GuHCl] for 16 amide protons show pronounced upward curvature, and a close inspection of the structure shows that these residues form a well-defined core in the protein. The hydrogen exchange that was measured at various concentrations of NaCl shows an apparent selective stabilisation of this core. Detailed analysis of this exchange pattern indicates that it may originate from selective destabilisation of the unfolded state by guanidinium ions and/or selective stabilisation of the core in the native state by chloride ions. © 2006 Elsevier Ltd. All rights reserved.

  • 9.
    Civitelli, Livia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nelson, Erin
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science.
    Iqbal Khattak, Sikander
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties2016In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 17, p. 9233-9243Article in journal (Refereed)
    Abstract [en]

    Aggregation of the amyloid-(beta) peptide (A beta) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the A beta peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the A beta fibrillation pathway may be a valid approach to reduce A beta cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic A beta species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting A beta-mediated cytotoxicity. Moreover, p-FTAA bound to early formed A beta species and induced a rapid formation of beta-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable A beta species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

  • 10.
    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.

  • 11.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Kanmert, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, p. 895-900Article in journal (Refereed)
    Abstract [en]

    The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the self-assembly process is an important factor in the development of Alzheimer’s disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptide-derived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

  • 12.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Otieno, Mildred
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Johansson, Leif B. G.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent ProbesManuscript (preprint) (Other academic)
    Abstract [en]

    The formation of soluble prefibrillar oligomeric species of the amyloid β peptide (Aβ) has been implicated as a causative agent in the development of Alzheimer’s disease (AD). It is therefore important to characterize the properties of these aggregates, which precede the formation of amyloid fibrils. We studied the in vitro aggregation process of two Aβ40 peptide variants through the combined use of four different fluorescent probes and transmission electron microscopy. Previous studies have shown that these two studied Aβ40 variants exhibit different levels of neurodegeneration when expressed in the central nervous system of Drosophila melanogaster. In the present study, we demonstrate distinct differences in aggregate morphology and their binding properties to different fluorescent probes during in vitro fibrillation of these Aβ peptides. Our results indicate a potential link between the observed neurodegenerative properties and the biophysical properties of distinct aggregated Aβ species.

  • 13.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Armstrong, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Garner, Brett
    Illawarra Health and Medical Research Institute University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    A protective role of lysozyme in Alzheimer diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

  • 14.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Bergkvist, Liza
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    SAP to the rescue: Serum amyloid p component ameliorates neurological damage caused by expressing a lysozyme variant in the central nervous system of Drosophila melanogasterManuscript (preprint) (Other academic)
    Abstract [en]

    Lysozyme amyloidosis is a hereditary disease in which mutations in the gene encoding lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT) lysozyme and the disease-associated variant F57I in the central nervous system (CNS) of a Drosophila melanogaster model of lysozyme amyloidosis, with and without serum amyloid p component (SAP). We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan and lower locomotor activity than flies expressing WT lysozyme or control flies, indicating that the flies’ neurological functions are impaired when F57I is expressed in the nerve cells. In addition, the Unfolded Protein Response (UPR) was upregulated in the F57I-expressing flies. However, co-expression of SAP in the CNS restored the F57I flies’ locomotor activity and lifespan. Thus, SAP has apparent ability to protect nerve cells from damage caused by F57I. Furthermore, co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies and delayed up-regulation of the UPR by 10 days in F57I flies. Our findings suggest that SAP can prevent cytotoxic effects of expressing F57I in fly CNS by retaining F57I in a soluble form and preventing crowding of misfolded F57I species in the endoplasmic reticulum.

  • 15.
    Helmfors, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, Faculty of Science & Engineering.
    Boman, Andrea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Civitelli, Livia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Sandin, Linnea
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    McCann, Heather
    Neuroscience Research Australia and University of New South Wales, Australia.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Halliday, Glenda
    UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease2015In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed)
    Abstract [en]

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

  • 16.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    In Vitro Amyloid Fibril Formation of Human IgG-FcManuscript (preprint) (Other academic)
    Abstract [en]

    Both light and heavy chains of human antibodies are known to be associated with immunoglobulin related amyloidosis, but in vitro formation of amyloid fibrils has previously only been reported for light chain sequences. Here we show that fibrillation of the Fc fragment of human IgG of all subclasses can be induced by heating to at least 75°C at neutral pH and physiological salt concentration. The observed protein assemblies share key properties with those constituting amyloid, i.e. they are thioflavinophilic and congophilic and have a typical fibril appearance in the transmission electron microscope. This study of the amyloidogenic properties of human IgG-Fc, comprising the CH2 and CH3 domains of the IgG heavy chain, is important for increasing the understanding of which parts of IgG that could be involved in amyloid formation in vivo.

  • 17.
    Kanmert, Daniel
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Thermal Induction of an Alternatively Folded State in Human IgG-Fc2011In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 50, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

    We report the formation of a non-native, folded state of human IgG4-Fc induced by a high temperature at neutral pH and at a physiological salt concentration. This structure is similar to the molten globule state in that it displays a high degree of secondary structure content and surface-exposed hydrophobic residues. However, it is highly resistant to chemical denaturation. The thermally induced state of human IgG4-Fc is thus associated with typical properties of the so-called alternatively folded state previously described for murine IgG, IgG-Fab, and individual antibody domains (V(L), V(H), C(H)1, and C(H)3) under acidic conditions in the presence of anions. Like some of these molecules, human IgG4-Fc in its alternative fold exists as a mixture of different oligomeric structures, dominated by an equilibrium between monomeric and heptameric species. Heating further induces the formation of fibrous structures in the micrometer range.

  • 18.
    Kumita, Janet R
    et al.
    University of Cambridge.
    Helmfors, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Williams, Jocy
    University of Cambridge.
    Luheshi, Leila M
    University of Cambridge.
    Menzer, Linda
    University of Liège.
    Dumoulin, Mireille
    University of Liège.
    Lomas, David A
    Cambridge Institute for Medical Research.
    Crowther, Damian C
    Cambridge Institute for Medical Research.
    Dobson, Christopher M
    University of Cambridge.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 1, p. 192-202Article in journal (Refereed)
    Abstract [en]

    We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster.

  • 19.
    Luheshi, Leila M
    et al.
    University of Cambridge.
    Hoyer, Wolfgang
    University of Gothenburg.
    de Barros, Teresa Pereira
    University of Cambridge.
    van Dijk Härd, Iris
    University of Gothenburg.
    Brorsson, Ann-Christin
    University of Cambridge.
    Macao, Bertil
    University of Gothenburg.
    Persson, Cecilia
    University of Gothenburg.
    Crowther, Damian C
    University of Cambridge.
    Lomas, David A
    University of Cambridge.
    Ståhl, Stefan
    Royal Institute of Technology (KTH), Stockholm.
    Dobson, Christopher M
    University of Cambridge.
    Härd, Torleif
    University of Gothenburg.
    Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo2010In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 3, p. e1000334-Article in journal (Refereed)
    Abstract [en]

    Protein aggregation, arising from the failure of the cell to regulate the synthesis or degradation of aggregation-prone proteins, underlies many neurodegenerative disorders. However, the balance between the synthesis, clearance, and assembly of misfolded proteins into neurotoxic aggregates remains poorly understood. Here we study the effects of modulating this balance for the amyloid-beta (Abeta) peptide by using a small engineered binding protein (Z(Abeta3)) that binds with nanomolar affinity to Abeta, completely sequestering the aggregation-prone regions of the peptide and preventing its aggregation. Co-expression of Z(Abeta3) in the brains of Drosophila melanogaster expressing either Abeta(42) or the aggressive familial associated E22G variant of Abeta(42) abolishes their neurotoxic effects. Biochemical analysis indicates that monomer Abeta binding results in degradation of the peptide in vivo. Complementary biophysical studies emphasize the dynamic nature of Abeta aggregation and reveal that Z(Abeta3) not only inhibits the initial association of Abeta monomers into oligomers or fibrils, but also dissociates pre-formed oligomeric aggregates and, although very slowly, amyloid fibrils. Toxic effects of peptide aggregation in vivo can therefore be eliminated by sequestration of hydrophobic regions in monomeric peptides, even when these are extremely aggregation prone. Our studies also underline how a combination of in vivo and in vitro experiments provide mechanistic insight with regard to the relationship between protein aggregation and clearance and show that engineered binding proteins may provide powerful tools with which to address the physiological and pathological consequences of protein aggregation.

  • 20.
    Luheshi, Leila M
    et al.
    Department of Chemistry, University of Cambridge.
    Tartaglia, Gian Gaetano
    Department of Chemistry, University of Cambridge.
    Brorsson, Ann-Christin
    Department of Chemistry, University of Cambridge.
    Pawar, Amol P
    Department of Chemistry, University of Cambridge.
    Watson, Ian E
    Department of Chemistry, University of Cambridge.
    Chiti, Fabrizio
    Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze.
    Vendruscolo, Michele
    Department of Chemistry, University of Cambridge.
    Lomas, David A
    Department of Medicine, University of Cambridge.
    Dobson, Christopher M
    Department of Chemistry, University of Cambridge.
    Crowther, Damian C
    Department of Genetics, University of Cambridge, Cambridge.
    Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.2007In: PLoS biology, ISSN 1545-7885, Vol. 5, no 11, p. e290-Article in journal (Refereed)
    Abstract [en]

    Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Abeta42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Abeta42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Abeta and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism.

  • 21.
    Macao, Bertil
    et al.
    Department of Medical Biochemistry, University of Gothenburg.
    Hoyer, Wolfgang
    Department of Medical Biochemistry, University of Gothenburg.
    Sandberg, Anders
    Department of Medical Biochemistry, University of Gothenburg.
    Brorsson, Ann-Christin
    Department of Chemistry, University of Cambridge.
    Dobson, Christopher M
    Department of Chemistry, University of Cambridge.
    Härd, Torleif
    Department of Medical Biochemistry, University of Gothenburg.
    Recombinant amyloid beta-peptide production by coexpression with an affibody ligand.2008In: BMC biotechnology, ISSN 1472-6750, Vol. 8, p. 82-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Oligomeric and fibrillar aggregates of the amyloid beta-peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). The characterization of Abeta assemblies is essential for the elucidation of the mechanisms of Abeta neurotoxicity, but requires large quantities of pure peptide. Here we describe a novel approach to the recombinant production of Abeta. The method is based on the coexpression of the affibody protein ZAbeta3, a selected affinity ligand derived from the Z domain three-helix bundle scaffold. ZAbeta3 binds to the amyloidogenic central and C-terminal part of Abeta with nanomolar affinity and consequently inhibits aggregation. RESULTS: Coexpression of ZAbeta3 affords the overexpression of both major Abeta isoforms, Abeta(1-40) and Abeta(1-42), yielding 4 or 3 mg, respectively, of pure 15N-labeled peptide per liter of culture. The method does not rely on a protein-fusion or -tag and thus does not require a cleavage reaction. The purified peptides were characterized by NMR, circular dichroism, SDS-PAGE and size exclusion chromatography, and their aggregation propensities were assessed by thioflavin T fluorescence and electron microscopy. The data coincide with those reported previously for monomeric, largely unstructured Abeta. ZAbeta3 coexpression moreover permits the recombinant production of Abeta(1-42) carrying the Arctic (E22G) mutation, which causes early onset familial AD. Abeta(1-42)E22G is obtained in predominantly monomeric form and suitable, e.g., for NMR studies. CONCLUSION: The coexpression of an engineered aggregation-inhibiting binding protein offers a novel route to the recombinant production of amyloidogenic Abeta peptides that can be advantageously employed to study the molecular basis of AD. The presented expression system is the first for which expression and purification of the aggregation-prone Arctic variant (E22G) of Abeta(1-42) is reported.

  • 22.
    Museth, Anna Katrine
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Brorsson, Anna-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Tibell, Lena A. E.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Selective destabilization of the metal binding region caused by the FALS associated mutation G93A in CuZnSODManuscript (preprint) (Other academic)
    Abstract [en]

    We have, by use of 1H-15N-HSQC NMR spectroscopy, analyzed hydrogen exchange at the amide groups of wtCuZnSOD and the FALS-associated G93A SOD-variant in their fully metallated states. From measurements at near physiological conditions we could analyze the exchange at 64% of all backbone amide groups, which have allowed a detailed characterization of the local dynamics at these positions in both the wt and G93A proteins. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However the mutation results in local destabilization at the site of mutation and to stabilization at positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may be involved in intermolecular protein-protein interactions, which may constitute the early stages in formation of aggregates.

  • 23.
    Museth, Anna Katrine
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology .
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Tibell, Lena
    Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    The ALS-Associated Mutation G93A in Human Copper-Zinc Superoxide Dismutase Selectively Destabilizes the Remote Metal Binding Region2009In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 48, no 37, p. 8817-8829Article in journal (Refereed)
    Abstract [en]

    More than 100 distinct mutations in the gene (SOD 1) for human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS). Studies of these mutant proteins, which often have been performed under far from physiological conditions, have indicated effects oil protein stabilities, catalytic activity, kind metal binding affinities but with no common pattern. Also, with the knowledge that ALS is a late onset disease it is apparent that protein interactions which contribute to the disorder might, in the natural cellular milieu, depend on a delicate balance between intrinsic protein properties. In this study, we have used experimental conditions as near as possible to the in vivo conditions to reduce artifacts emanating from the experimental setup. Using H-1-N-15 HSQC NMR spectroscopy, we have analyzed hydrogen exchange at the amide groups of wild-type (wt) CuZnSOD and the fALS-associated G93A SOD variant in their fully metalated states. From analyses of the exchange pattern, we have characterized the local dynamics at 64% of all positions in detail in both the wt and G93A protein. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However, the mutation results in local destabilization at the site of the Mutation and also in stabilization at a few positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may affect the intermolecular protein-protein interactions which cause formation of protein aggregates.

  • 24.
    Nystrom, Sofie
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nelson, Erin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Reitan, Nina
    Norwegian University of Science and Technology.
    Ellingsen, Pal
    Norwegian University of Science and Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Mason, Jeffrey
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Johansson, Leif
    Linköping University, Department of Physics, Chemistry and Biology, Semiconductor Materials. Linköping University, The Institute of Technology.
    Sluzny, Chanan
    Appl Spectral Imaging, Migdal Haemeq.
    Handrick, Susann
    Charite.
    Prokop, Stefan
    Charite.
    Wegenast-Braun, Bettina
    German Centre Neurodegenerat Disease.
    Hornemann, Simone
    University of Zurich Hospital.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Lindgren, Mikael
    Norwegian University of Science and Technology.
    Heppner, Frank
    Charite.
    Jucker, Mathias
    German Centre Neurodegenerat Disease.
    Aguzzi, Adriano
    University of Zurich Hospital.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Monitoring amyloid formation and maturation in vitro and in vivo using LCO fluorescence in PRION, vol 6, issue , pp 13-132012In: PRION, Landes Bioscience , 2012, Vol. 6, p. 13-13Conference paper (Refereed)
    Abstract [en]

    n/a

  • 25.
    Yanamandra, Kiran
    et al.
    Department of Medical Biochemistry and Biophysics, Umeå University.
    Alexeyev, Oleg
    Department of Medical Biosciences/Pathology, Umeå University.
    Zamotin, Vladimir
    Department of Medical Biochemistry and Biophysics, Umeå University.
    Srivastava, Vaibhav
    Umeå Plant Science Center, Umeå University.
    Shchukarev, Andrei
    Department of Chemistry, Umeå University.
    Brorsson, Ann-Christin
    Department of Chemistry, University of Cambridge.
    Tartaglia, Gian Gaetano
    Department of Chemistry, University of Cambridge.
    Vogl, Thomas
    Institute of Immunology, University of Münster.
    Kayed, Rakez
    Department of Neurology, University of Texas.
    Wingsle, Gunnar
    Umeå Plant Science Center, Umeå University.
    Olsson, Jan
    Department of Medical Biosciences/Pathology, Umeå University.
    Dobson, Christopher M
    Department of Chemistry, University of Cambridge.
    Bergh, Anders
    Department of Medical Biosciences/Pathology, Umeå University.
    Elgh, Fredrik
    Department of Clinical Microbiology/Virology, Umeå University.
    Morozova-Roche, Ludmilla A
    Department of Medical Biochemistry and Biophysics, Umeå University.
    Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate.2009In: PloS one, ISSN 1932-6203, Vol. 4, no 5, p. e5562-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon--prostate tissue remodelling in middle-aged and elderly men. METHODOLOGY/PRINCIPAL FINDINGS: By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. CONCLUSIONS/SIGNIFICANCE: These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.

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