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BETA
Berg, Ina
Alternative names
Publications (6 of 6) Show all publications
Ceasar (Berg), I., Jonsson, M., Nilsson, P., Thor, S. & Hammarström, P. (2012). Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila. PLoS ONE, 7(2)
Open this publication in new window or tab >>Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed) Published
Abstract [en]

The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-73502 (URN)10.1371/journal.pone.0031424 (DOI)000302733900047 ()
Note
funding agencies|Knut and Alice Wallenberg foundation||Swedish Foundation for Strategic Research||Hjarnfonden||Swedish Research Council||Gustaf V. foundation||European Union||Available from: 2012-01-05 Created: 2012-01-05 Last updated: 2018-04-25
Berg, I., Nilsson, P., Thor, S. & Hammarström, P. (2010). Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses. Nature Protocols, 5(5), 935-944
Open this publication in new window or tab >>Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses
2010 (English)In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 5, p. 935-944Article in journal (Refereed) Published
Abstract [en]

Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.

Place, publisher, year, edition, pages
Macmillan Publishers Ltd., 2010
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-55024 (URN)10.1038/nprot.2010.41 (DOI)000277174100012 ()
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2018-04-25Bibliographically approved
Berg, I. (2010). Modeling Amyloid Disease in Drosophila melanogaster. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Modeling Amyloid Disease in Drosophila melanogaster
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid diseases are caused by protein misfolding and aggregation. To date there are 27 known proteins causing amyloid disorders involving brain and peripheral protein deposition. The proteins involved in this mechanism do not share sequence homology, but the amyloid fibrils share biophysical properties and possibly a common pathogenic mechanism. Amyloid deposits are known to be involved in a broad range of neurodegenerative diseases, such as Alzheimer’s disease and Creutzfeldt-Jakob disease, as well as in non-neuropathic diseases, such as senile systemic amyloidosis and type II diabetes.

During the last decade the fruit fly, Drosophila melanogaster (Drosophila), have increasingly been used as a model for neurodegenerative disease, such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and familial amyloidotic polyneuropathy. The advantages of using the Drosophila model are the well-defined genetic characteristics, the quantity, short life span, simplicity in genetic manipulation and the powerful binary UAS-Gal4 transgenic system. The UAS-Gal4 system allows for rapid generation of individual strains in which expression of a specific gene of interest can be directed to different tissues or cell types. The system allows the target gene to be activated in different cell- and tissue-types by altering the activator-expressing lines.

This thesis has been focused on modeling amyloid diseases in Drosophila. This has been performed by:

  • Creating new model systems of senile systemic amyloidosis and familial amyloidotic polyneuropathy in Drosophila
  • Developing a new staining protocol for detection of amyloid in Drosophila
  • Initiate a compound screen of Alzheimer’s disease modeled in Drosophila
Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. p. 88
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1320
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-55025 (URN)978-91-7393-379-7 (ISBN)
Public defence
2010-05-21, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 09:15 (English)
Opponent
Supervisors
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2020-02-19Bibliographically approved
Berg, I., Thor, S. & Hammarström, P. (2009). Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in Drosophila melanogaster. NEURODEGENERATIVE DISEASES, 6(3), 127-138
Open this publication in new window or tab >>Modeling Familial Amyloidotic Polyneuropathy (Transthyretin V30M) in Drosophila melanogaster
2009 (English)In: NEURODEGENERATIVE DISEASES, ISSN 1660-2854, Vol. 6, no 3, p. 127-138Article in journal (Refereed) Published
Abstract [en]

Background/Aims: Transthyretin (TTR) is a prevalent plasma and cerebrospinal fluid protein associated with sporadic and heritable amyloidosis. TTR amyloidosis is linked to a vast number of mutations with varying phenotype, tissue distribution and age of onset. The most prevalent mutation associated with familial amyloidotic polyneuropathy (FAP) is the V30M mutation. Studies of transgenic mouse models of TTR V30M FAP have been hampered by variable phenotype, low disease penetrance, and slow onset. Methods/Results: To model TTR-associated amyloid disease in the Drosophila model system, transgenic Drosophila were generated, expressing wild-type (wt) TTR or TTR V30M, associated with sporadic senile systemic amyloidosis (SSA) and inherited FAP, respectively. We found that expression of FAP-associated TTR V30M mutant in the nervous system resulted in reduced lifespan and in reduced climbing ability indicating neurological impairment, whereas expression of TTR wt showed a milder phenotype. Congo red staining of the Drosophila brain shows positive amyloid binding in the aged TTR V30M flies. Extensive brain vacuole formation was evident for the aged TTR V30M flies, whereas a milder phenotype was shown by the TTR wt flies. In addition, expression of TTR V30M in the eye leads to tissue damage, including rough eye, morphological changes and fibrous deposition. Conclusion: Our results suggest that Drosophila is a promising complementary system for studies of TTR-associated amyloid diseases.

Keywords
Amyloid disease, Drosophila melanogaster, Transthyretin, Familial amyloidotic polyneuropathy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18382 (URN)10.1159/000213761 (DOI)
Available from: 2009-05-25 Created: 2009-05-25 Last updated: 2018-04-25
Sörgjerd, K., Wiseman, R. L., Kågedal, K., Berg, I., Klingstedt, T., Budka, H., . . . Hammarström, P.BiP can function as a molecular shepherd that alleviates oligomer toxicity and amass amyloid.
Open this publication in new window or tab >>BiP can function as a molecular shepherd that alleviates oligomer toxicity and amass amyloid
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(English)Manuscript (Other academic)
Abstract [en]

A wide range of diseases are linked to protein misfolding and aggregation inside and outside the cell. It is of utmost interest to understand how the molecular chaperone machinery of the endoplasmic reticulum (ER) handles the expression of highly amyloidogenic proteins. We explored the hypothesis that the ER located Hsp70 molecular chaperone BiP plays a crucial role in amyloid diseases and influence the misfolding process and disease progression. We used the transthyretin mutant TTR D18G associated with an unusual central nervous system amyloid disease as the model substrate because it represents the most destabilized and degraded TTR variant known. Over-expression of TTR D18G in concert with BiP showed that BiP selectively recognize the amyloidogenic mutant protein as compared to wild type in human cells and collects the mutant in stable intermediate size oligomers within the ER. Furthermore, whereas TTR D18G was found to be highly cytotoxic to neuroblastoma cells, TTR D18G preincubated with BiP was non-toxic indicating that BiP protects the cell from cytotoxicity. BiP was also found present in cerebellar amyloid deposits and co-localized with TTR in a TTR D18G patient suggesting that the complex can be found in the extracellular space. We promote a fundamental role of BiP in misfolding diseases and describe a molecular shepharding function of BiP in sequestrating amyloidogenic protein molecules in benign oligomeric states.

Keywords
Amyloid, transthyretin, chaperone, misfolding, oligomer, cytotoxicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-12564 (URN)
Available from: 2008-09-15 Created: 2008-09-15 Last updated: 2018-04-25
Berg, I., Nilsson, P., Thor, S. & Hammarström, P.Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic Drosophila.
Open this publication in new window or tab >>Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic Drosophila
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Curcumin has been proposed to facilitate clearance of toxic amyloid formed by the Aβ peptide. To further address this notion, different concentrations of curcumin were tried for its effects in various Drosophila Alzheimer’s disease (AD) models. This study entailed five different Drosophila AD models (four Aβ expressing lines, and one tau expressing line), expressing the AD associated proteins using the Gal4/UAS system. These were assayed for several aspects of neurological impairment, including survival, climbing behavior, as well as locomotor activity. In addition, amyloid deposition was assessed by histological analysis. Curcumin treatment substantially prolonged the lifespan and improved climbing and locomotor activity for flies with severe disease geneotypes (Aβ1-42 E22G and double expressing Aβ1-42). In comparison, curcumin feeding of control flies resulted in a concentration-dependent shortened lifespan, whereas no such toxic side effects were found for AD genotypes with a mild phenotype (single expressors of Aβ1-40 and Aβ1-42). All flies expressing Aβ and tau displayed a higher total locomotor activity, and a continuation of the activity over a larger number of hours upon curcumin treatment. Unexpectedly, no change in tissue amyloid deposition upon curcumin treatment was observed. In vitro fibrillation of Aβ1-42, followed by Western blot and transmission electron microscopy in the presence and absence of curcumin, displayed enhanced fibrillation into large aggregates and decreased population of oligomers in curcumin samples. The decrease in oligomer formation by curcumin may explain why it increases the lifespan and activity without removing of the amyloid deposits seen in tissues. We also suggest that Aβ, at least in the context of Drosophila, functions as a chemical detoxifier sequestering curcumin and thereby mitigating its toxicity.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-55020 (URN)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2018-04-25
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