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A? exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease

A? exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease
A? exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease
Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Abeta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric Abeta(42) are responsible for the neuronal dysfunction and cognitive impairments that underlie the early stages of AD, but the mechanism by which they interact in the pathogenic process is not clear. Mounting evidence suggests that Abeta(42) pathology lies upstream of hyper-phosphorylated tau pathology. Similarly much is being learnt about how each protein affects neuronal function. However, the impact that either pathological protein has on neuronal dysfunction caused by the other is not extensively studied. We have investigated this in a Drosophila model of AD in which we express both phosphorylated human tau (tau(wt)) and oligomeric Abeta(42). We find that expression of tau(wt) causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of Abeta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/Abeta(42) and flies with LiCl ameliorates the exacerbating effect of Abeta(42), suggesting that GSK-3beta may be involved in the mechanism by which Abeta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of Abeta(42), mimicking the wingless signalling pathway by co-expression of dishevelled with tau(wt) reduces tau phosphorylation and suppresses the tau-mediated phenotypes. It is therefore possible to speculate that the mechanism by which Abeta(42) interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling
animal model, axonal transport, drosophila model, GSK-3?, synaptic dysfunction, wnt/wingless signalling
0014-4886
1-9
Folwell, James
fdc794a1-45a8-44ef-88d6-fa44bf9908cb
Cowan, Catherine M.
9dd8dfb6-bfa9-4388-b386-8e98e188b22a
Ubhi, Kiren K.
1dc81fd9-dd3c-4d8a-a631-1155f378571e
Shiabh, Hassan
6fe95eee-1bbf-4153-8442-66c7f009aeed
Newman, Tracey A.
322290cb-2e9c-445d-a047-00b1bea39a25
Shepherd, David
11aa6858-d19c-4450-82ff-11dff9dcd9c4
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Folwell, James
fdc794a1-45a8-44ef-88d6-fa44bf9908cb
Cowan, Catherine M.
9dd8dfb6-bfa9-4388-b386-8e98e188b22a
Ubhi, Kiren K.
1dc81fd9-dd3c-4d8a-a631-1155f378571e
Shiabh, Hassan
6fe95eee-1bbf-4153-8442-66c7f009aeed
Newman, Tracey A.
322290cb-2e9c-445d-a047-00b1bea39a25
Shepherd, David
11aa6858-d19c-4450-82ff-11dff9dcd9c4
Mudher, Amritpal
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119

Folwell, James, Cowan, Catherine M., Ubhi, Kiren K., Shiabh, Hassan, Newman, Tracey A., Shepherd, David and Mudher, Amritpal (2009) A? exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease. Experimental Neurology, 223 (2), 1-9. (doi:10.1016/j.expneurol.2009.09.014).

Record type: Article

Abstract

Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Abeta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric Abeta(42) are responsible for the neuronal dysfunction and cognitive impairments that underlie the early stages of AD, but the mechanism by which they interact in the pathogenic process is not clear. Mounting evidence suggests that Abeta(42) pathology lies upstream of hyper-phosphorylated tau pathology. Similarly much is being learnt about how each protein affects neuronal function. However, the impact that either pathological protein has on neuronal dysfunction caused by the other is not extensively studied. We have investigated this in a Drosophila model of AD in which we express both phosphorylated human tau (tau(wt)) and oligomeric Abeta(42). We find that expression of tau(wt) causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of Abeta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/Abeta(42) and flies with LiCl ameliorates the exacerbating effect of Abeta(42), suggesting that GSK-3beta may be involved in the mechanism by which Abeta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of Abeta(42), mimicking the wingless signalling pathway by co-expression of dishevelled with tau(wt) reduces tau phosphorylation and suppresses the tau-mediated phenotypes. It is therefore possible to speculate that the mechanism by which Abeta(42) interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling

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More information

Submitted date: 6 April 2009
Published date: 24 September 2009
Keywords: animal model, axonal transport, drosophila model, GSK-3?, synaptic dysfunction, wnt/wingless signalling
Organisations: Faculty of Medicine, Centre for Biological Sciences

Identifiers

Local EPrints ID: 72702
URI: https://eprints.soton.ac.uk/id/eprint/72702
ISSN: 0014-4886
PURE UUID: 02d92f51-fe91-465a-922d-78a17db6d15a
ORCID for Tracey A. Newman: ORCID iD orcid.org/0000-0002-3727-9258

Catalogue record

Date deposited: 19 Feb 2010
Last modified: 07 Aug 2019 00:50

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