Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease
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 amylo...
Published in: | PLoS Genetics |
---|---|
Main Authors: | , , , , , , , , , |
Format: | Text |
Language: | English |
Published: |
Public Library of Science
2010
|
Subjects: | |
Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932684 http://www.ncbi.nlm.nih.gov/pubmed/20824130 https://doi.org/10.1371/journal.pgen.1001087 |
id |
ftpubmed:oai:pubmedcentral.nih.gov:2932684 |
---|---|
record_format |
openpolar |
spelling |
ftpubmed:oai:pubmedcentral.nih.gov:2932684 2023-05-15T15:13:07+02:00 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 2010-09 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932684 http://www.ncbi.nlm.nih.gov/pubmed/20824130 https://doi.org/10.1371/journal.pgen.1001087 en eng Public Library of Science http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932684 http://www.ncbi.nlm.nih.gov/pubmed/20824130 http://dx.doi.org/10.1371/journal.pgen.1001087 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. CC-BY Research Article Text 2010 ftpubmed https://doi.org/10.1371/journal.pgen.1001087 2013-09-03T04:20:38Z 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. Text Arctic PubMed Central (PMC) Arctic PLoS Genetics 6 9 e1001087 |
institution |
Open Polar |
collection |
PubMed Central (PMC) |
op_collection_id |
ftpubmed |
language |
English |
topic |
Research Article |
spellingShingle |
Research Article Sofola, Oyinkan Kerr, Fiona Rogers, Iain Killick, Richard Augustin, Hrvoje Gandy, Carina Allen, Marcus J. Hardy, John Lovestone, Simon Partridge, Linda Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
topic_facet |
Research Article |
description |
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. |
format |
Text |
author |
Sofola, Oyinkan Kerr, Fiona Rogers, Iain Killick, Richard Augustin, Hrvoje Gandy, Carina Allen, Marcus J. Hardy, John Lovestone, Simon Partridge, Linda |
author_facet |
Sofola, Oyinkan Kerr, Fiona Rogers, Iain Killick, Richard Augustin, Hrvoje Gandy, Carina Allen, Marcus J. Hardy, John Lovestone, Simon Partridge, Linda |
author_sort |
Sofola, Oyinkan |
title |
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
title_short |
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
title_full |
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
title_fullStr |
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
title_full_unstemmed |
Inhibition of GSK-3 Ameliorates Aβ Pathology in an Adult-Onset Drosophila Model of Alzheimer's Disease |
title_sort |
inhibition of gsk-3 ameliorates aβ pathology in an adult-onset drosophila model of alzheimer's disease |
publisher |
Public Library of Science |
publishDate |
2010 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932684 http://www.ncbi.nlm.nih.gov/pubmed/20824130 https://doi.org/10.1371/journal.pgen.1001087 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932684 http://www.ncbi.nlm.nih.gov/pubmed/20824130 http://dx.doi.org/10.1371/journal.pgen.1001087 |
op_rights |
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. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1371/journal.pgen.1001087 |
container_title |
PLoS Genetics |
container_volume |
6 |
container_issue |
9 |
container_start_page |
e1001087 |
_version_ |
1766343710458511360 |