Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease.
Folwell, James, Cowan, Catherine M., Ubhi, Kiren K., Shiabh, Hassan, Newman, Tracey A., Shepherd, David and Mudher, Amritpal (2009) Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease. Experimental Neurology, 1-9. (doi:10.1016/j.expneurol.2009.09.014).
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Description/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
| Item Type: | Article |
|---|---|
| ISSNs: | 0014-4886 (print) |
| Related URLs: | |
| Keywords: | animal model, axonal transport, drosophila model, GSK-3β, synaptic dysfunction, wnt/wingless signalling |
| Subjects: | R Medicine > RB Pathology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Clinical Neurosciences University Structure - Pre August 2011 > School of Biological Sciences |
| Item ID: | 72702 |
| Date Deposited: | 19 Feb 2010 |
| Last Modified: | 02 Mar 2012 11:52 |
| Contributors: | Folwell, James (Author) Cowan, Catherine M. (Author) Ubhi, Kiren K. (Author) Shiabh, Hassan (Author) Newman, Tracey A. (Author) Shepherd, David (Author) Mudher, Amritpal (Author) |
| Date: | 24 September 2009 |
| Status: | Published |
| Contact Email Address: | a.mudher@soton.ac.uk |
| URI: | http://eprints.soton.ac.uk/id/eprint/72702 |
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