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Published on: August 3, 2021
Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity
Stanislav Ott1, Anastasia Vishnivetskaya1, Anders Malmendal2
1Department of Genetics, University of Cambridge, Cambridge, UK.
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 shibire(TS) 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.
Insights
Alzheimer's disease-linked amyloid beta (Aβ) shortens fruit fly lifespan, but not by disrupting proteostasis. Lethality is linked to oxidative stress and respiration dysfunction in aging flies.
Area of Science:
- Neuroscience
- Aging Research
- Molecular Biology
Background:
- Amyloid beta (Aβ) peptide aggregation is a key factor in Alzheimer's disease pathogenesis.
- Aggregation-prone Aβ isoforms expressed in the brain reduce lifespan in Drosophila melanogaster, but effects manifest after 15 days.
- Proteostatic robustness, the ability to maintain protein homeostasis, is crucial for cellular health during aging.
Purpose of the Study:
- To investigate the mechanism by which amyloid beta (Aβ) causes lethality in Drosophila melanogaster.
- To determine if Aβ exerts its lethal effects through proteostatic disruption.
- To explore the relationship between aging, Aβ expression, and metabolic changes, particularly oxidative stress.
Main Methods:
- Utilized shibire(TS) flies, a temperature-sensitive paralysis model, to assess proteostatic robustness.
- Administered chemical challenges, focusing on oxidative stressors, to differentiate between young and old flies.
- Employed nuclear magnetic resonance (NMR) spectroscopy and multivariate analysis to compare metabolomic profiles of flies with and without Aβ expression at different ages.
Main Results:
- Increasing age, not Aβ expression, lowered the permissive temperature in shibire(TS) flies, indicating Aβ does not primarily disrupt proteostasis.
- Oxidative stressors effectively distinguished between young (robust) and old (sensitive) flies.
- Metabolomic analysis revealed genotype-linked signals correlating with Aβ presence and the specific Arctic Aβ isoform.
- Lethality in Aβ-expressing flies was strongly associated with impaired oxidative respiration and heightened oxidative stress.
Conclusions:
- Amyloid beta (Aβ) mediated lethality in Drosophila is not due to proteostatic disruption but is linked to aging-related sensitivity.
- Metabolomic profiling identified distinct signatures associated with Aβ expression and its isoforms.
- The findings highlight a critical role for oxidative respiration dysfunction and oxidative stress in Aβ-induced lethality, providing insights into Alzheimer's disease mechanisms.
