Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing drosophila larval model of Alzheimer's Disease.
Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing drosophila larval model of Alzheimer's Disease.
Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway.
Sinadinos, Christopher
fcc3580b-a0db-4060-91b7-8ce102a0af69
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Sealey, Megan
d90c98bf-c535-4f9f-9bd4-7e60d59477a1
Samson, P. Benjamin
6cc26577-0f48-4f05-9383-25b83bcc1960
Mudher, Amrit
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
2013
Sinadinos, Christopher
fcc3580b-a0db-4060-91b7-8ce102a0af69
Quraishe, Shmma
cfc3aed4-f120-41aa-9127-0fc26c657ad2
Sealey, Megan
d90c98bf-c535-4f9f-9bd4-7e60d59477a1
Samson, P. Benjamin
6cc26577-0f48-4f05-9383-25b83bcc1960
Mudher, Amrit
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Wyttenbach, Andreas
05019897-52b1-4bb6-b259-5d51abae7540
Sinadinos, Christopher, Quraishe, Shmma, Sealey, Megan, Samson, P. Benjamin, Mudher, Amrit and Wyttenbach, Andreas
(2013)
Low endogenous and chemical induced heat shock protein induction in a 0N3Rtau-expressing drosophila larval model of Alzheimer's Disease.
Journal of Alzheimer's Disease, 33 (4).
(PMID:23114515)
Abstract
Reduction of tau phosphorylation and aggregation by manipulation of heat shock protein (HSP) molecular chaperones has received much attention in attempts to further understand and treat tauopathies such as Alzheimer's disease. We examined whether endogenous HSPs are induced in Drosophila larvae expressing human tau (3R-tau) in motor neurons, and screened several chemical compounds that target the HSP system using medium-throughput behavioral analysis to assay their effects on tau-induced neuronal dysfunction in vivo. Tau-expressing larvae did not show a significant endogenous HSP induction response, whereas robust induction of hsp70 was detectable in a similar larval model of polyglutamine disease. Although pan-neuronal tau expression augmented the induction of hsp70 following heat shock, several candidate HSP inducing compounds induced hsp70 protein in mammalian cells in vitro but did not detectably induce hsp70 mRNA or protein in tau expressing larvae. The hsp90 inhibitors 17-AAG and radicicol nevertheless caused a dose-dependent reduction in total human tau levels in transgenic larvae without specifically altering tau hyperphosphorylated at S396/S404. These and several other HSP modulating compounds also failed to rescue the tau-induced larval locomotion deficit in this model. Tau pathology in tau-expressing larvae, therefore, induces weak de novo HSP expression relative to other neurodegenerative disease models, and unlike these disease models, pharmacological manipulation of the hsp90 pathway does not lead to further induction of the heat shock response. Forthcoming studies investigating the effects of HSP induction on tau-mediated dysfunction/toxicity in such models will require more robust, non-pharmacological (perhaps genetic) means of manipulating the hsp90 pathway.
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Published date: 2013
Organisations:
Centre for Biological Sciences
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Local EPrints ID: 345540
URI: http://eprints.soton.ac.uk/id/eprint/345540
ISSN: 1387-2877
PURE UUID: 22155c49-a528-4c1b-8475-286d956f35d6
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Date deposited: 26 Nov 2012 14:56
Last modified: 28 Jul 2022 01:41
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Author:
Christopher Sinadinos
Author:
Megan Sealey
Author:
P. Benjamin Samson
Author:
Andreas Wyttenbach
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