P1-066: Dietary restriction delays ageing, but not neuronal pathology, in drosophila models of Alzheimer's disease

Abstract

Dietary restriction (DR) extends lifespan in diverse organisms and can delay a range of ageing-related diseases including Alzheimer's disease (AD), whereas high-fat diets are suggested to be an important environmental risk factor for AD. Moreover, several studies in mice have suggested that diet can alter the molecular mechanisms underlying AD pathology; caloric restriction (CR) reduces Aβ and tau pathologies and improves cognitive function, whereas high-fat diets have been shown to increase Aβ pathology in mouse models of AD. A better understanding of the mechanisms mediating these interactions, however, may reveal novel pathways involved in AD pathogenesis, and potential targets for preventative treatment and biomarkers for disease progression. Drosophila models of AD have recently been developed and, due to their short life-span and susceptibility to genetic manipulation, we have used the fly to investigate the connections between diet, ageing and AD pathology. Arctic mutant Aβ42 or WT 4R tau-overexpressing flies were subjected to dietary manipulation, by dilution of the nutrients in a standard sugar-yeast (SY) food medium, and the effects on lifespan, negative geotaxis and biochemical phenotypes analysed. DR delayed lifespan in both Arctic Aβ42 and tau-overexpressing flies, but the neuronal dysfunction (climbing ability) and biochemical (Aβ42 accumulation and tau phosphorylation) phenotypes analysed were unaltered by dietary manipulation. Our data suggests that DR may alter ageing through generalised mechanisms independent of the specific pathways underlying AD pathogenesis. On the other hand, these observations are in contrast to previously published studies which have shown that CR can improve cognitive function, prevent amyloid accumulation and reduce tau phosphorylation in mouse models of AD. One possibility for this discrepancy is that the mechanisms underlying the effects of DR on ageing may vary between organisms. Alternatively, the difference may be explained by the suggestion that diet alters Aβ toxicity upstream of peptide production, by regulating the activities of α- and γ-secretase enzymes, in mouse models of APP-cleavage. γ-secretase reporter flies will, therefore, be used to examine whether our dietary manipulation regime alters γ-secretase activity in Drosophila, similarly to previous observations in mice, and this data will be presented.