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

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.

Amyloid β42 peptide is toxic to non-neural cells inDrosophilayielding a characteristic metabolite profile and the effect can be suppressed by PI3K

“…Increased histidine levels were observed in response to acute stress and artificial selection for stress resistance in Drosophila ( Malmendal et al, 2013 ; Overgaard et al, 2007 ). Histidine has earlier been shown to increase in Drosophila expressing both benign and toxic Aβ ( Ott et al, 2016 ), which is very similar to the present system where histidine increased in Aβ42 flies, independent of co-expression of PI3K. In humans, high histidine was found in urine from patients with Parkinson's disease ( Luan et al, 2015 ), and additional high levels of lysine were found in plasma from patients with mild cognitive impairment ( Trushina et al, 2013 ).…”

“…The Aβ42-induced metabolite changes agree with those caused by toxic Arctic Aβ42 (E22G) relative to non-toxic levels of Aβ42 and Aβ40 in abdomens ( Ott et al, 2016 ) in that we see an increase in histidine and a decrease in maltose in both systems ( Fig. 4 B,C).…”

“…Fly models of AD show changes in the metabolite profile both in nervous and non-nervous tissues ( Ott et al, 2016 ). Thus, we explored the metabolome of adult flies expressing high levels of Aβ42, either alone or in combination with PI3K.…”

“…Maltose has been suggested to have a chaperone-like function ( Kaplan and Guy, 2004 ; Pereira and Hünenberger, 2006 ) and increased levels were observed in Drosophila expressing non-toxic levels of Aβ40 and Aβ42 and in short and long-term stress responses ( Ott et al, 2016 ; Malmendal et al, 2013 ; Overgaard et al, 2007 ). Uridine is precursor of phosphatidylcholine, a major component of cellular membranes, and a reduction in cerebrum-spinal fluid (CSF) of AD patients was suggested to be linked to neuronal deficits ( Czech et al, 2012 ).…”

Hemolymph metabolites and osmolality are tightly linked to cold tolerance ofDrosophilaspecies: a comparative study

“…The accumulation of maltose in the chill-susceptible species could therefore function to reduce the likelihood of chill injury following cold exposure, but may also be a more general and non-specific response to stressful conditions. Increased levels of maltose have previously been linked to a wide range of different stressors like inbreeding, thermal stress, starvation and artificial expression of the amyloid β-peptide (Pedersen et al, 2008;Malmendal et al, 2013;Ott et al, 2016).…”