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BETA
Brorsson, Ann-Christin
Alternative names
Publications (10 of 25) Show all publications
Civitelli, L., Sandin, L., Nelson, E., Iqbal Khattak, S., Brorsson, A.-C. & Kågedal, K. (2016). The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties. Journal of Biological Chemistry, 291(17), 9233-9243
Open this publication in new window or tab >>The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 17, p. 9233-9243Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-128747 (URN)10.1074/jbc.M115.696229 (DOI)000374849000033 ()26907684 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Torsten Soderberg Foundation; Alzheimer Foundation; Dementia Foundation; Linkoping University Neurobiology Center

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2018-03-20
Helmfors, L., Boman, A., Civitelli, L., Nath, S., Sandin, L., Janefjord, C., . . . Kågedal, K. (2015). Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease. Neurobiology of Disease, 83, 122-133
Open this publication in new window or tab >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Domert, J., Rao, S. B., Agholme, L., Brorsson, A.-C., Marcusson, J., Hallbeck, M. & Nath, S. (2014). Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance. Neurobiology of Disease, 65, 82-92
Open this publication in new window or tab >>Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
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2014 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Alzheimer's disease, Amyloid-β oligomers, Cell-to-cell transfer, Intracellular accumulation, Prion-like propagation
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-103179 (URN)10.1016/j.nbd.2013.12.019 (DOI)000333546300008 ()24412310 (PubMedID)
Available from: 2014-01-14 Created: 2014-01-14 Last updated: 2019-10-14Bibliographically approved
Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., . . . Brorsson, A.-C. (2012). Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster. The FASEB Journal, 26(1), 192-202
Open this publication in new window or tab >>Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
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2012 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 1, p. 192-202Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Federation of American Society of Experimental Biology (FASEB), 2012
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-73186 (URN)10.1096/fj.11-185983 (DOI)000299202200020 ()21965601 (PubMedID)
Note

funding agencies|Swedish Research Council||Biotechnology and Biological Sciences Research Council| BB/E019927/1 BBH0038431 |Wellcome Trust||Leverhulme Trust||European Commission| LSHM-CT-2006-037525/EURAMY |Medical Research Council| G0700990 |VINNOVA||

Available from: 2011-12-21 Created: 2011-12-21 Last updated: 2017-12-08
Göransson, A.-L., Kanmert, D., Nilsson, K. P., Kågedal, K. & Brorsson, A.-C. (2012). Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants. Biochemical and Biophysical Research Communications - BBRC, 420(4), 895-900
Open this publication in new window or tab >>Identification of distinct physiochemical properties of the toxic prefibrillar species formed by Aβ peptide variants
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2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 420, no 4, p. 895-900Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-73185 (URN)10.1016/j.bbrc.2012.03.097 (DOI)000303619100034 ()
Note

funding agencies|Swedish National Graduate School in Science, Technology and Mathematics Education Research (Fon-tD)||Swedish Alzheimers Foundation||Soderberg foundation||

Available from: 2011-12-21 Created: 2011-12-21 Last updated: 2017-12-08Bibliographically approved
Nystrom, S., Nelson, E., Reitan, N., Ellingsen, P., Brorsson, A.-C., Mason, J., . . . Hammarström, P. (2012). Monitoring amyloid formation and maturation in vitro and in vivo using LCO fluorescence in PRION, vol 6, issue , pp 13-13. In: PRION: . Paper presented at Prion2012 (pp. 13-13). Landes Bioscience, 6
Open this publication in new window or tab >>Monitoring amyloid formation and maturation in vitro and in vivo using LCO fluorescence in PRION, vol 6, issue , pp 13-13
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2012 (English)In: PRION, Landes Bioscience , 2012, Vol. 6, p. 13-13Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Landes Bioscience, 2012
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-78587 (URN)000304234300027 ()
Conference
Prion2012
Available from: 2012-06-15 Created: 2012-06-15 Last updated: 2018-04-25
Kanmert, D., Brorsson, A.-C., Jonsson, B.-H. & Enander, K. (2011). Thermal Induction of an Alternatively Folded State in Human IgG-Fc. Biochemistry, 50(6), 981-988
Open this publication in new window or tab >>Thermal Induction of an Alternatively Folded State in Human IgG-Fc
2011 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 50, no 6, p. 981-988Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society, 2011
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-65532 (URN)10.1021/bi101549n (DOI)000287049500008 ()21261247 (PubMedID)
Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2017-12-11Bibliographically approved
Brorsson, A.-C., Bolognesi, B., Tartaglia, G. G., Shammas, S. L., Favrin, G., Watson, I., . . . Luheshi, L. M. (2010). Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide. Biophysical Journal, 98(8), 1677-84
Open this publication in new window or tab >>Intrinsic determinants of neurotoxic aggregate formation by the amyloid beta peptide
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2010 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 8, p. 1677-84Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-60811 (URN)10.1016/j.bpj.2009.12.4320 (DOI)20409489 (PubMedID)
Available from: 2010-10-27 Created: 2010-10-27 Last updated: 2017-12-12
Brorsson, A.-C., Kumita, J. R., MacLeod, I., Bolognesi, B., Speretta, E., Luheshi, L. M., . . . Crowther, D. C. (2010). Methods and models in neurodegenerative and systemic protein aggregation diseases. Frontiers in bioscience : a journal and virtual library, 15, 373-396
Open this publication in new window or tab >>Methods and models in neurodegenerative and systemic protein aggregation diseases
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2010 (English)In: Frontiers in bioscience : a journal and virtual library, ISSN 1093-4715, Vol. 15, p. 373-396Article, review/survey (Refereed) Published
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.

Place, publisher, year, edition, pages
Frontiers in Bioscience Publications, 2010
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-57011 (URN)000282619800026 ()20036826 (PubMedID)
Available from: 2010-06-14 Created: 2010-06-09 Last updated: 2010-10-29
Luheshi, L. M., Hoyer, W., de Barros, T. P., van Dijk Härd, I., Brorsson, A.-C., Macao, B., . . . Härd, T. (2010). Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo. PLoS biology, 8(3), e1000334
Open this publication in new window or tab >>Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo
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2010 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 3, p. e1000334-Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-60812 (URN)10.1371/journal.pbio.1000334 (DOI)20305716 (PubMedID)
Available from: 2010-10-27 Created: 2010-10-27 Last updated: 2017-12-12
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