Metabolic changes precede proteostatic dysfunction in a Drosophila model of Abeta peptide toxicity

Stanislav Ott, Anastasia Vishnivetskaya, Anders Malmendal, Damian C. Crowther

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibireTS flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress.
OriginalsprogEngelsk
TidsskriftNeurobiology of Aging
Vol/bind41
Sider (fra-til)39-52
Antal sider14
ISSN0197-4580
DOI
StatusUdgivet - maj 2016
Udgivet eksterntJa

Citer dette

Ott, Stanislav ; Vishnivetskaya, Anastasia ; Malmendal, Anders ; Crowther, Damian C. / Metabolic changes precede proteostatic dysfunction in a Drosophila model of Abeta peptide toxicity. I: Neurobiology of Aging. 2016 ; Bind 41. s. 39-52.
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abstract = "Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibireTS flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress.",
author = "Stanislav Ott and Anastasia Vishnivetskaya and Anders Malmendal and Crowther, {Damian C.}",
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Metabolic changes precede proteostatic dysfunction in a Drosophila model of Abeta peptide toxicity. / Ott, Stanislav; Vishnivetskaya, Anastasia; Malmendal, Anders; Crowther, Damian C.

I: Neurobiology of Aging, Bind 41, 05.2016, s. 39-52.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Metabolic changes precede proteostatic dysfunction in a Drosophila model of Abeta peptide toxicity

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AU - Vishnivetskaya, Anastasia

AU - Malmendal, Anders

AU - Crowther, Damian C.

PY - 2016/5

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N2 - Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibireTS flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress.

AB - Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibireTS flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress.

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DO - 10.1016/j.neurobiolaging.2016.01.009

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JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

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