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Inhibition of GSK-3 ameliorates Aβ pathology in an adult-onset drosophila model of Alzheimer's Disease

Sofola, O; Kerr, F; Rogers, I; Killick, R; Augustin, H; Gandy, C; Allen, MJ; ... Partridge, L; + view all (2010) Inhibition of GSK-3 ameliorates Aβ pathology in an adult-onset drosophila model of Alzheimer's Disease. PLoS Genetics , 6 (9) , Article e1001087. 10.1371/journal.pgen.1001087. Green open access

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Abstract

A beta 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 A beta 42 specifically in adult neurons, to avoid developmental effects. A beta 42 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 A beta 42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued A beta 42 toxicity. A beta 42 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 A beta 42. The GSK-3-mediated effects on A beta 42 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, A beta 42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of A beta 42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates A beta 42 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.

Type: Article
Title: Inhibition of GSK-3 ameliorates Aβ pathology in an adult-onset drosophila model of Alzheimer's Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1001087
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1001087
Language: English
Additional information: © 2010 Sofola et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Glycogen-synthase kinase-3, App transgenic mice, In-vivo, Tau phosphorylation, Protein-tau, Neurofibrillary tangles, Signaling pathway, Memory deficits, Premature death, Mouse model
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/1302796
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