Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues

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Jonsson, MariaLinköpings universitet,Kemi,Tekniska fakulteten (author)

Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues

Article/chapterEnglish2015

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2015-07-24
Public Library of Science,2015
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LIBRIS-ID:oai:DiVA.org:liu-120740
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-120740URI
https://doi.org/10.1371/journal.pone.0133272DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Funding Agencies|Swedish VINNOVA; King Gustaf Vs and Queen Victorias Freemasons Foundation; AstraZeneca, Sodertalje; Swedish Research Council; VINNOVA grant, "Innovations for future health"
Brain amyloid plaques are a hallmark of Alzheimers disease (AD), and primarily consist of aggregated A beta peptides. While A beta 1-40 and A beta 1-42 are the most abundant, a number of other A beta peptides have also been identified. Studies have indicated differential toxicity for these various A beta peptides, but in vivo toxicity has not been systematically tested. To address this issue, we generated improved transgenic Drosophila UAS strains expressing 11 pertinent A beta peptides. UAS transgenic flies were generated by identical chromosomal insertion, hence removing any transgenic position effects, and crossed to a novel and robust Gal4 driver line. Using this improved Gal4/UAS set-up, survival and activity assays revealed that A beta 1-42 severely shortens lifespan and reduces activity. N-terminal truncated peptides were quite toxic, with 3-42 similar to 1-42, while 11-42 showed a pronounced but less severe phenotype. N-terminal mutations in 3-42 (E3A) or 11-42 (E11A) resulted in reduced toxicity for 11-42, and reduced aggregation for both variants. Strikingly, C-terminal truncation of A beta (1-41, -40, -39, -38, -37) were non-toxic. In contrast, C-terminal extension to 1-43 resulted in reduced lifespan and activity, but not to the same extent as 1-42. Mutating residue 42 in 1-42 (A42D, A42R and A42W) greatly reduced A beta accumulation and toxicity. Histological and biochemical analysis revealed strong correlation between in vivo toxicity and brain A beta aggregate load, as well as amount of insoluble A beta. This systematic Drosophila in vivo and in vitro analysis reveals crucial N- and C-terminal specificity for A beta neurotoxicity and aggregation, and underscores the importance of residues 1-10 and E11, as well as a pivotal role of A42.

Subject headings and genre

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng

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Pokrzywa, MalgorzataLinköpings universitet,Medicinska fakulteten,Avdelningen för mikrobiologi och molekylär medicin(Swepub:liu)malpo25 (author)
Starkenberg, AnnikaLinköpings universitet,Avdelningen för mikrobiologi och molekylär medicin,Medicinska fakulteten(Swepub:liu)annst28 (author)
Hammarström, PerLinköpings universitet,Kemi,Tekniska fakulteten(Swepub:liu)perha81 (author)
Thor, StefanLinköpings universitet,Avdelningen för mikrobiologi och molekylär medicin,Medicinska fakulteten(Swepub:liu)steth80 (author)
Linköpings universitetKemi (creator_code:org_t)

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In:PLOS ONE: Public Library of Science10:71932-6203

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