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

Kerr, Fiona; Rogers, Iain; Martinez, Pedro; Hardy, John; Lovestone, Simon; Partridge, Linda

Abstract

Background
Ageing is the major risk factor for the development of many neurodegenerative diseases, including Alzheimer's Disease (AD). One of the major unresolved questions in the AD field asks why neurodegeneration occurs late in life. This association could reflect the length or degree of exposure to toxic proteins required for pathology to occur, or could indicate that the ageing process itself increases the susceptibility of neurons to protein toxicity. We aimed to resolve these possibilities by expressing a standard dose of Aß42 at different ages and measuring the time to develop, and extent of, subsequent pathological phenotypes.

Methods
We used the Drosophila GeneSwitch (GS) inducible system to express the Arctic Ab42 peptide in young versus old fly neurons. The degree of Arctic Aß42 over-expression was modulated by altering the concentration and length of exposure to the inducer mifepristone (RU486). Lifespan was then measured as a surrogate marker of Ab42 toxicity in ageing flies.

Results
Older flies were more vulnerable to Aß42 toxicity than young flies, as they displayed the largest reduction in lifespan following induction of the peptide under both chronic and standardised conditions.

Conclusions
Our results imply that the late age-of-onset of neurodegeneration is likely to be a consequence of the ageing process increasing neuronal vulnerability to proteotoxicity. Future work will analyse the solubility of Aß42 peptide in young and old flies, to further our understanding of the relationship between protein aggregation and toxicity with age.

• Presentation Conference Type: Conference Abstract
• Conference Name: Alzheimer 's Association International Conference 2012
• Start Date: Jul 14, 2012
• Publication Date: 2012-07
• Deposit Date: May 2, 2024
• Journal: Alzheimer's & Dementia
• Print ISSN: 1552-5260
• Electronic ISSN: 1552-5279
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 4S_Part_6
• Pages: P202
• DOI: https://doi.org/10.1016/j.jalz.2012.05.554