Ageing Increases Vulnerability to Aβ42 Toxicity in Drosophila

Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's Disease (AD), for reasons that are not clear. The association could indicate that the duration or degree of exposure to toxic proteins is important for pathology, or that age itself increases susceptibility to protein toxicity. Using an inducible Drosophila model of AD, we investigated these possibilities by varying the expression of an A beta 42 transgene in neurons at different adult ages and measuring the effects on A beta 42 levels and associated pathological phenotypes. Acute induction of Arctic A beta 42 in young adult flies resulted in rapid expression and clearance of mRNA and soluble Arctic A beta 42 protein, but in irreversible expression of insoluble Arctic A beta 42 peptide. Arctic A beta 42 peptide levels accumulated with longer durations of induction, and this led to a dose-dependent reduction in negative geotaxis and lifespan. For a standardised level of mRNA expression, older flies had higher levels of Arctic A beta 42 peptide and associated toxicity, and this correlated with an age-dependent reduction in proteasome activity. Equalising A beta 42 protein at different ages shortened lifespan in correlation with the duration of exposure to the peptide, suggesting that A beta 42 expression accumulates damage over time. However, the relative reduction in lifespan compared to controls was greater in flies first exposed to the peptide at older ages, suggesting that ageing itself also increases susceptibility to A beta 42 toxicity. Indeed older flies were more vulnerable to chronic A beta 42 toxicity even with a much lower lifetime exposure to the peptide. Finally, the persistence of insoluble A beta 42 in both young and old induced flies suggests that aggregated forms of the peptide cause toxicity in later life. Our results suggest that reduced protein turnover, increased duration of exposure and increased vulnerability to protein toxicity at later ages in combination could explain the late age-of-onset of neurodegenerative phenotypes.