Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease

Sofola, Oyinkan; Kerr, Fiona; Rogers, Iain; Killick, Richard; Augustin, Hrvoje; Gandy, Carina; Allen, Marcus J.; Hardy, John; Lovestone, Simon; Partridge, Linda

Abstract

Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.

• Journal Article Type: Article
• Acceptance Date: Aug 5, 2009
• Online Publication Date: Sep 2, 2010
• Publication Date: Sep 2, 2010
• Deposit Date: Oct 26, 2016
• Journal: PLoS Genetics
• Print ISSN: 1553-7390
• Electronic ISSN: 1553-7404
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 9
• Article Number: e1001087
• DOI: https://doi.org/10.1371/journal.pgen.1001087
• Public URL: http://researchrepository.napier.ac.uk/Output/355761