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

NEUROBIOLOGY OF AGING

卷:41

Article

Ott, Stanislav¹  Vishnivetskaya, Anastasia¹  Malmendal, Anders²  Crowther, Damian C.^1,3 

[1] Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England

[2] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen N, Denmark

[3] MedImmune Ltd, Neurosci IMED, Granta Pk, Cambridge, England

关键词: Drosophila;    Aging;    Metabolomics;    Amyloid beta;    Proteostasis;   

DOI  :  10.1016/j.neurobiolaging.2016.01.009

来源: Elsevier

【 摘 要 】

Amyloid beta (A beta) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of A beta, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of A beta 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 beta expression lowered the flies' permissive temperature, suggesting that A beta 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 beta in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any A beta isoform and the second the effects of the lethal Arctic A beta. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress. (C) 2016 The Authors. Published by Elsevier Inc.

【 授权许可】

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