P1‐274: Ageing increases vulnerability to Aβ42 toxicity in drosophila

Abstract

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 Ab42 transgene in neurons at different adult ages and measuring the effects on Ab42 levels and associated pathological phenotypes. Acute induction of Arctic Ab42 in young adult flies resulted in rapid expression and clearance of mRNA and soluble Arctic Ab42 protein, but in irreversible expression of insoluble Arctic Ab42 peptide. Arctic Ab42 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 Ab42 peptide and associated toxicity, and this correlated with an age-dependent reduction in proteasome activity. Equalising Ab42 protein at different ages shortened lifespan in correlation with the duration of exposure to the peptide, suggesting that Ab42 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 Ab42 toxicity. Indeed older flies were more vulnerable to chronic Ab42 toxicity even with a much lower lifetime exposure to the peptide. Finally, the persistence of insoluble Ab42 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.