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

• Main Authors: Oyinkan Sofola, Fiona Kerr, Iain Rogers, Richard Killick, Hrvoje Augustin, Carina G
• Other Authors: The Pennsylvania State University CiteSeerX Archives
• Format: Text
• Language: English
• Subjects: Arctic
• Online Access: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.352.1148

Ab 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 Ab42 specifically in adult neurons, to avoid developmental effects. Ab42 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 Ab42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Ab42 toxicity. Ab42 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 Ab42. The GSK-3–mediated effects on Ab42 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, Ab42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Ab42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Ab42 levels in the fly and to determine if similar mechanisms are