liu.seSearch for publications in DiVA
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila
Linköpings universitet, Institutionen för fysik, kemi och biologi, Proteinkemi. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Proteinkemi. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Organisk Kemi. Linköpings universitet, Tekniska högskolan.ORCID-id: 0000-0002-5582-140X
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0001-5095-541X
Vise andre og tillknytning
2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 2Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Public Library of Science , 2012. Vol. 7, nr 2
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-73502DOI: 10.1371/journal.pone.0031424ISI: 000302733900047OAI: oai:DiVA.org:liu-73502DiVA, id: diva2:473237
Merknad
funding agencies|Knut and Alice Wallenberg foundation||Swedish Foundation for Strategic Research||Hjarnfonden||Swedish Research Council||Gustaf V. foundation||European Union||Tilgjengelig fra: 2012-01-05 Laget: 2012-01-05 Sist oppdatert: 2018-04-25
Inngår i avhandling
1. Investigating Amyloid β toxicity in Drosophila melanogaster
Åpne denne publikasjonen i ny fane eller vindu >>Investigating Amyloid β toxicity in Drosophila melanogaster
2017 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

In this thesis Drosophila melanogaster (the fruit fly) has been used as a model organism to study the aggregation and toxic properties of the human amyloid β (Aβ) peptide involved in the onset of Alzheimer's disease (AD). AD is one of many misfolding diseases where the important event of a protein to adopt its’ specific three-dimensional structure has failed, leading to aggregation and formation of characteristic amyloid fibrils. AD has a complex pathology and probably reflects a variety of related molecular and cellular abnormalities, however, the most apparent common denominator so far is abnormal Amyloid-β precursor protein (APP) processing, resulting in a pool of various Aβ-peptides. In AD, the Aβ peptide misfolds, aggregates and forms amyloid plaques in the brain of patients, resulting in progressive neurodegeneration that eventually leads to death.

By expressing the human Aβ protein in the fly, we have studied the mechanisms and toxicity of the aggregation in detail and how different cell types in the fly are affected. We have also used this model to investigate the effect of potential drugs that can have a positive impact on disease progression. In the first and second work in this thesis, we have, in a systematic way, proved that the length of the Aβ-peptide is essential for its toxicity and propensity to aggregate. If the peptide expressed ends at amino acid 42 it is extremely toxic to the fly nervous system. However, this toxicity can be completely abolished by expressing a variant that is shorter than 42 amino acids (1-37 to 1-41 aa), or be significantly reduced by expressing a longer variant (1-43 aa). Toxicity can be partly mitigated in trans by co-expressing the 1-42 variant with a 1-38 variant. This supports the theory that the disease progression could be inhibited if the formation of Aβ 1-42 is decreased. In the third work we demonstrate that amyloid aggregates can be found in various cell types of Drosophila, however, the toxicity seem to be selective to neurons. Our results indicate that the aggregates of glial expressing flies have a more mature structure, which appear to be less toxic. This also suggests that glial cells might spread Aβ aggregates without being harmed. The last work in this thesis investigates how curcumin (turmeric) can affect Aβ aggregation and toxicity. Curcumin appears to shift the equilibrium between the less stable

aggregates and mature fibers toward the final stage resulting in an improved lifespan for treated flies.

In summary, this thesis demonstrates that the toxicity of Aβ in Drosophila is highly dependent on the Aβ variant expressed, the structure of the protein aggregates and which cell type that expresses the protein. We have also shed light on the potential of using Drosophila when it comes to examining possible therapeutic substances as a tool for drug discovery.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2017. s. 88
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1859
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-138389 (URN)10.3384/diss.diva-138389 (DOI)9789176855089 (ISBN)
Disputas
2017-06-09, Planck, Fysikhuset, Campus Valla, Linköping, 14:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-06-14 Laget: 2017-06-14 Sist oppdatert: 2019-10-11bibliografisk kontrollert

Open Access i DiVA

fulltext(1242 kB)378 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 1242 kBChecksum SHA-512
6b718e67c3ad4474b708e9b36739b306ceaf17c50fe9f87ceba138b7d9d12433f16b5896596486e0a15669c0420a61fe174a5a8c0ec892d5041f27231a14f2d5
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekst

Personposter BETA

Ceasar (Berg), InaJonsson, MariaNilsson, PeterThor, StefanHammarström, Per

Søk i DiVA

Av forfatter/redaktør
Ceasar (Berg), InaJonsson, MariaNilsson, PeterThor, StefanHammarström, Per
Av organisasjonen
I samme tidsskrift
PLoS ONE

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 378 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
urn-nbn

Altmetric

doi
urn-nbn
Totalt: 791 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf