Amyloid β42 peptide is toxic to non-neural cells in<i>Drosophila</i>yielding a characteristic metabolite profile and the effect can be suppressed by PI3K

Arnés, Mercedes; Casas‐Tintó, Sergio; Malmendal, Anders; Ferrús, Alberto

doi:10.1242/bio.029991

Cited by 5 publications

(3 citation statements)

References 70 publications

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“…In the other models, human AβPP is co‐expressed with human BACE1 allowing the production of C99 and different isoforms of the Aβ peptide (including post‐translationally modified Aβ variants) through the processing of human AβPP by human BACE1 and by endogenous fly γ‐secretase (the AβPP‐BACE1 fly model) . AD fly models have been frequently used during the last two decades to investigate Aβ toxicity, cell‐specific vulnerability and aggregation . However, potential differences in the toxic mechanisms between the two different AD fly models have not been thoroughly investigated.…”

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confidence: 99%

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease

Bergkvist

Elovsson

et al. 2020

FEBS Open Bio

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Alzheimer's 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 Aβ fly model and the AβPP‐BACE1 fly model. In the Aβ fly model, the Aβ peptide is fused to a secretion sequence and directly overexpressed. In the AβPP‐BACE1 model, human AβPP and human BACE1 are expressed in the fly, resulting in in vivo production of Aβ peptides and other AβPP 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 Aβ fly model, this correlates with high Aβ1–42 levels and down‐regulation of the levels of mRNA encoding lysosomal‐associated membrane protein 1, lamp1 (a lysosomal marker), while in the AβPP‐BACE1 fly model, neuronal cell death correlates with low Aβ1–42 levels, up‐regulation of lamp1 mRNA levels and increased levels of C‐terminal fragments. In addition, a significant amount of AβPP/Aβ antibody (4G8)‐positive species, located close to the endosomal marker rab5, was detected in the AβPP‐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.

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confidence: 99%

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease

Bergkvist

Elovsson

et al. 2020

FEBS Open Bio

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“…At the same time, it was shown that the negative effects of Aβ are not tissue-specific. The expression of the human Aβ42 peptide in adult Drosophila in a tissue- and time-controlled manner revealed that Aβ42 is also toxic in different non-neural cell types, including neurosecretory and epithelial cells [ 39 ]. The toxic effect may be associated with the Aβ-induced oxidative stress [ 14 ], as was evidenced by an increase in the expression level of Prx5 .…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β peptides slightly affect lifespan or antimicrobial peptide gene expression in Drosophila melanogaster

et al. 2020

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Background Beta-amyloid peptide (Aβ) is the key protein in the pathogenesis of Alzheimer’s disease, the most common age-related neurodegenerative disorder in humans. Aβ peptide induced pathological phenotypes in different model organisms include neurodegeneration and lifespan decrease. However, recent experimental evidence suggests that Aβ may utilize oligomerization and fibrillization to function as an antimicrobial peptide (AMP), and protect the host from infections. We used the power of Drosophila model to study mechanisms underlying a dual role for Aβ peptides. Results We investigated the effects of Drosophila treatment with three Aβ42 peptide isoforms, which differ in their ability to form oligomers and aggregates on the lifespan, locomotor activity and AMP genes expression. Aβ42 slightly decreased female’s median lifespan (by 4.5%), but the effect was not related to the toxicity of peptide isoform. The lifespan and relative levels of AMP gene expression in male flies as well as locomotor activity in both sexes were largely unaffected by Aβ42 peptide treatment. Regardless of the effects on lifespan, Aβ42 peptide treatment induced decrease in AMP genes expression in females, but the effects were not robust. Conclusions The results demonstrate that chronic treatment with Aβ42 peptides does not drastically affect fly aging or immunity.

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“…Synapse-promoting actions of PI3K are age-independent, as their activation at different times along adulthood generates new, supernumerary and fully functional synapses (Martín-Peña et al, 2006;Acebes et al, 2011. Recently, we reported the protective activity of PI3K over the Aβ42 toxicity caused in nonneuronal cells (Arnés et al, 2017). Unraveling the mechanisms that underlie these protective effects of PI3K would be of potential therapeutic interest, in particular if the early onset of AD could be diagnosed.…”

Section: Introductionmentioning

confidence: 99%

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposit formation

Arnés

Romero

Casas‐Tintó

et al. 2020

MBoC

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Amyloid β42 peptide is toxic to non-neural cells inDrosophilayielding a characteristic metabolite profile and the effect can be suppressed by PI3K

Cited by 5 publications

References 70 publications

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease

Mapping pathogenic processes contributing to neurodegeneration in Drosophila models of Alzheimer's disease

Amyloid-β peptides slightly affect lifespan or antimicrobial peptide gene expression in Drosophila melanogaster

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposit formation

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