Abstract
Dietary restriction (DR) extends lifespan in diverse organisms and, in animal and cellular models, can delay a range of aging-related diseases including Alzheimer's disease (AD). A better understanding of the mechanisms mediating these interactions, however, may reveal novel pathways involved in AD pathogenesis, and potential targets for disease-modifying treatments and biomarkers for disease progression. Drosophila models of AD have recently been developed and, due to their short lifespan and susceptibility to genetic manipulation, we have used the fly to investigate the molecular connections among diet, aging and AD pathology. DR extended lifespan in both Arctic mutant Aβ42 and WT 4R tau over-expressing flies, but the underlying molecular pathology was not altered and neuronal dysfunction was not prevented by dietary manipulation. Our data suggest that DR may alter aging through generalised mechanisms independent of the specific pathways underlying AD pathogenesis in the fly, and hence that lifespan-extending manipulations may have varying effects on aging and functional declines in aging-related diseases. Alternatively, our analysis of the specific effects of DR on neuronal toxicity downstream of Aβ and tau pathologies with negative results may simply confirm that the neuro-protective effects of DR are upstream of the initiating events involved in the pathogenesis of AD.
Highlights
Alzheimer’s disease (AD) is a highly prevalent and devastating aging-related condition
WT 4R tau overexpressing flies did not differ in lifespan from the upstream activator sequence (UAS)-WT 4R tau transgene control (Fig. 1D), survival of both of these lines was substantially reduced in comparison to the elav GAL4 driver line
Leaky expression of tau in tissues other than neurons may account for the reduction in lifespan of both the UAS-control line and the tau over-expressing flies compared to the GAL4 line alone
Summary
Alzheimer’s disease (AD) is a highly prevalent and devastating aging-related condition. AD patients display progressive cognitive decline, including deficits in memory, Abbreviations: DR, dietary restriction; AD, Alzheimer’s disease; A, amyloid-beta; NFT, neurofibrillary tangle; APP, amyloid precursor protein; FAD, familial Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; IIS, insulin/IGF-like signalling; IF, intermittent fasting; AL, ad libitum; SY, sugar-yeast; WT, wild-type; UAS, upstream activator sequence; PI, performance index; DT, decline time; GFS, giant fibre system; GF, giant fibre; TTM, tergotrochanteral muscle; DLM, dorsal longitudinal flight muscle. F. Kerr et al / Neurobiology of Aging 32 (2011) 1977–1989 the study of model organisms suggests that this is the case. Attenuation of insulin-like signalling (IIS) and dietary restriction both extend lifespan and protect against A and, in the case of DR, against other types of proteotoxicity in genetic models of disease in the nematode worm Caenorhabditis elegans (Cohen et al, 2006; Steinkraus et al, 2008). Investigation of the molecular mechanisms by which ameliorating the aging process can protect against AD pathology should highlight important pathways involved in the initiation of sporadic AD pathogenesis, and lead to the discovery of novel targets for disease-modifying therapies and biomarkers for the progression of the disease
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