Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity.

ABSTRACT: Amyloid beta (A?) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of A?, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of A? 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 A? expression lowered the flies' permissive temperature, suggesting that A? 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 A? in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any A? isoform and the second the effects of the lethal Arctic A?. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress.

SUBMITTER: Ott S 

PROVIDER: S-EPMC4869574 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature