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Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimers disease
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Van Andel Res Inst, MI USA.
Univ Cambridge, England; Univ Cambridge, England.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
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2020 (Engelska)Ingår i: FEBS Open Bio, E-ISSN 2211-5463, Vol. 10, nr 3, s. 338-350Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Alzheimers disease (AD) is the most common form of dementia, affecting millions of people and currently lacking available disease-modifying treatments. Appropriate disease models are necessary to investigate disease mechanisms and potential treatments. Drosophila melanogaster models of AD include the A beta fly model and the A beta PP-BACE1 fly model. In the A beta fly model, the A beta peptide is fused to a secretion sequence and directly overexpressed. In the A beta PP-BACE1 model, human A beta PP and human BACE1 are expressed in the fly, resulting in in vivo production of A beta peptides and other A beta PP cleavage products. Although these two models have been used for almost two decades, the underlying mechanisms resulting in neurodegeneration are not yet clearly understood. In this study, we have characterized toxic mechanisms in these two AD fly models. We detected neuronal cell death and increased protein carbonylation (indicative of oxidative stress) in both AD fly models. In the A beta fly model, this correlates with high A beta(1-42) levels and down-regulation of the levels of mRNA encoding lysosomal-associated membrane protein 1, lamp1 (a lysosomal marker), while in the A beta PP-BACE1 fly model, neuronal cell death correlates with low A beta(1-42) levels, up-regulation of lamp1 mRNA levels and increased levels of C-terminal fragments. In addition, a significant amount of A beta PP/A beta antibody (4G8)-positive species, located close to the endosomal marker rab5, was detected in the A beta PP-BACE1 model. Taken together, this study highlights the similarities and differences in the toxic mechanisms which result in neuronal death in two different AD fly models. Such information is important to consider when utilizing these models to study AD pathogenesis or screening for potential treatments.

Ort, förlag, år, upplaga, sidor
WILEY , 2020. Vol. 10, nr 3, s. 338-350
Nyckelord [en]
Alzheimers disease; amyloid-beta; Drosophila melanogaster; endo-lysosomal system; neurodegeneration
Nationell ämneskategori
Strukturbiologi
Identifikatorer
URN: urn:nbn:se:liu:diva-163625DOI: 10.1002/2211-5463.12773ISI: 000508510400001PubMedID: 31823504OAI: oai:DiVA.org:liu-163625DiVA, id: diva2:1393862
Anmärkning

Funding Agencies|Torsten Soderberg Foundation; Apotekare Hedbergs Foundation; Ahlens Foundation; Swedish Alzheimer Foundation; Swedish Dementia Foundation; Frimurarestiftelsen; Centre for Misfolding Diseases; Herchel Smith PhD Research Scholarship; Rosetrees TrustRosetrees Trust

Tillgänglig från: 2020-02-17 Skapad: 2020-02-17 Senast uppdaterad: 2021-04-20

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Bergkvist, LizaElovsson, GretaAppelqvist, HannaKågedal, KatarinaBrorsson, Ann-Christin
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