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Inhibition of GSK-3 ameliorates Ab pathology in an adult-onset Drosophila model of Alzheimer’s disease

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posted on 2023-06-09, 08:33 authored by Oyinkan Adesakin, Fiona Kerr, Iain Rogers, Richard Killick, Hrvoje Augustin, Carina Gandy, Marcus Allen, John Hardy, Simon Lovestone, Linda Partridge
Aß 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 Aß42 specifically in adult neurons, to avoid developmental effects. Aß42 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 Aß42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aß42 toxicity. Aß42 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 Aß42. The GSK-3–mediated effects on Aß42 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, Aß42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aß42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aß42 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS Genetics

ISSN

1553-7390

Publisher

Public Library of Science

Issue

9

Volume

6

Department affiliated with

  • Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-11-02

First Open Access (FOA) Date

2017-11-02

First Compliant Deposit (FCD) Date

2017-11-01

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