How does hyper-phosphorylated tau cause nerve cell degeneration?
Institution: University of Southampton
Grant type: Project
Duration: 3 years (+ 9 month no-cost extension)
Start date: February 2009
Completion date: October 2012
Scientific Title: How does hyper-phosphorylated tau mediate breakdown of the microtubular cytoskeleton? Can this be prevented by exogenous and endogenous interventions? Does this protect against tau toxicity?
What was the project, and what did the researchers do?
Using a fruit fly model of Alzheimer’s disease, Dr Mudher and her team have shown that in the presence of the abnormal human tau protein the ‘tracks’ inside nerve cells, over which material is usually transported, break down. One of the aims of this grant was to shed light on the mechanism by which these tracks break down.
Another aim of this research was to work out whether agents that can ‘Sellotape’ the collapsed tracks together may be used to prevent the disruption of transport inside these nerves.
The researchers used an established fruit fly model that produces abnormal tau, the researchers were able to investigate how this tau behaves in certain conditions.
What were the key results, and how will this help in the fight against dementia?
The researchers have shown that the abnormal human tau is not able to attach to the tracks as it should and this is one of the reasons why they collapse in its presence.
They have found that agents such as Paclitaxel and NAP10, which are know to bind to and stick together microtubules (tubes within a cell, including tau, that make up its skeleton), are able to improve the behaviour of fruit fly larvae that are expressing the abnormal human tau.
The researchers found that there are many more intact tracks in NAP10 treated tau flies than in untreated flies. They then went on to show that transport of materials over the more intact tracks in the treated tau flies is dramatically improved and looks very similar to what it is in normal flies.
These results imply that treatment with the drug that can stick tracks together has the ability to reverse all the detrimental effects of abnormal tau: reinstating the broken tracks, improving the transport of materials over them and then leading to improvements in behaviour of the animals. These results provide exciting new avenues of research for the development of drugs to fight Alzheimer's disease.
Additionally, the researchers have continued to investigate whether increasing the amount of ‘anti-stress’ proteins such as ’chaperones’ (which belong to a class of proteins that normally get produced in cells in stressful situations) may protect the nerve cells from the damaging effects of the abnormal human tau.
We have generated flies that express both human tau and a chaperone protein and we find that these flies are much more resilient to the toxic effects of human tau than flies expressing the human tau alone. The experiments we have conducted so far have used oxygen deprivation as a means of stressing the flies and we find that many of the tau expressing flies die soon after this stress and those that survive are not able to fly or climb about easily. However, the flies that express both the human tau and chaperone are remarkably different to the tau flies without the chaperone – none of chaperone/tau flies died after this stress and most of them regained their climbing and flying abilities. These results are preliminary but clearly suggest that if one way of overcoming the toxic effects of human tau may be to increase the amount of anti-stress responses in the cell – like increasing the amount of chaperone proteins.
What happened next? Future work and additional grants
The researchers had begun to repeat the preliminary studies involving the chaperone fruit fly model, but due to time constraints were unable to complete them. Perhaps this will be the subject of a future grant.
Dr Mudher also currently holds another Alzheimer's Society grant, and her team will be working to better understand exactly how tau causes brain cells to die.
How were people told about the results? Conferences and publications
- Under review: Microtubule stabilisation protects against tau-mediated dysfunction in a Drosophila model of tauopathy. Shmma Quraishe, Catherine Cowan and Amrit Mudher Manuscript in review Molecular Psychiatry Dec 2012.
Conferences and oral presentations:
- Biochemical Society Focused meeting, University of Cambridge Jan 2012 - Modulation of the microtubule cytoskeleton in a Drosophila model of Tauopathy. S Quraishe, Cowan CM and Mudher A. Poster presentation.
- Integrative Approaches to Developing Therapeutics for Neurodegenerative Diseases. University of Cardiff (Aug 2012) - NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. S Quraishe, Cowan CM and Mudher A. Selected Oral presentation.
- BRAIN AGEING AND DEMENTIA IN DEVELOPING COUNTRIES (Dec 2012) Nairobi, Kenya. NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. S Quraishe, Cowan CM and Mudher A. Invited talk.