Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity.
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.
Department of Genetics, University of Cambridge, Cambridge, UK.
Stanislav
S
Ott
Department of Genetics, University of Cambridge, Cambridge, UK.
Anastasia
A
Vishnivetskaya
Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark. Electronic address: malmendal@sund.ku.dk.
Anders
A
Malmendal
Department of Genetics, University of Cambridge, Cambridge, UK; Neuroscience IMED, MedImmune Limited, Granta Park, Cambridge, UK. Electronic address: damian.crowther@azneuro.com.
Damian C
DC
Crowther
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D018384:Oxidative Stress; D020033:Protein Isoforms / Q000378:metabolism / Q000633:toxicity; D057165:Proteostasis Deficiencies / Q000209:etiology* / Q000378:metabolism*; D013696:Temperature
D016229:Amyloid beta-Peptides; D020033:Protein Isoforms
Aging; Amyloid beta; Drosophila; Metabolomics; Proteostasis