Lead Investigator: Dr Amritpal Mudher
Institution: Southampton University
Grant type: Project
Start Date: October 2010
Completion Date: October 2013
Scientific Title: Which attributes of tau mediate toxicity: Expression levels or Aggregation?
What was the project, and what did the researchers do?
During Alzheimer's disease an abnormal version of a protein called tau accumulates as tangles or clumps inside nerve cells. Some scientists believe that this abnormal tau is linked to the death of brain cells.
In an earlier project, Dr Mudher's team found evidence that tau clumps may not be responsible for damage to cells. In that project, they used flies bred to have the human abnormal tau protein. This causes the flies to display some Alzheimer-like symptoms, such as difficulty with movement. When the researchers treated these flies with drugs that altered the structure of the tau protein, they found that the flies' symptoms improved. But they were surprised to find that after this treatment many clumps in the flies' brains were similar to those found in the brains of people with Alzheimer's. This result suggested these clumps may not be toxic at all. The researchers suggested that it is the structure of the tau protein and not the clumping that may be toxic.
In this project, the researchers built on this finding. They examined the clumps more closely to confirm whether they were tau and to look at their structure. They also used some more flies that were specially bred to try to show if it was the structure of the tau that caused the toxicity.
The findings of this study may provide more evidence that tau clumps are not themselves toxic. The researchers may also be able to suggest how the structure of tau may explain its toxicity.
What were the key results, and how will this help in the fight against dementia?
Dr Mudher was able to confirm that the clumps found in the flies' brains were likely to be made of the tau protein, and were very similar to the clumps found in the brains of people living with Alzheimer's.
The researchers also studied the structure of the tau protein. The drug treatment that improved the flies' symptoms changed the tau protein through a process called dephosphorylation. They demonstrated that tau proteins that had not undergone this process may be toxic to nerve cells and that the flies had Alzheimer-like symptoms, even when there were low levels of tau or there were no tau-clumps.
These findings offer more understanding of the underlying causes of Alzheimer's disease. They also suggest new drug targets that alter the structure of the tau protein.
What happened next? Future work and additional grants
Dr Mudher has applied for further funding to continue to investigate this research.
How were people told about the results? Conferences and publications
Rescue from tau-induced neuronal dysfunction produces insoluble tau-oligomers. Cowan CM et al. Nature Scientific Reports. 2015 Nov. 5:17191
What is the pathological significance of tau oligomers? Cowan CM, Quraishe S, Mudher A. Biochem Soc Trans. 2012 Aug;40(4):693
What is the pathological significance of tau aggregation? Cowan CM and Mudher A. Invited review to Frontiers of Neurology May 2013.
11th International conference Alzheimer's disease and Parkinson's disease. March 2013 Florence, Italy. Invited talk.
Pathobiology of PSP - Focused meeting. March 2013 London, UK. Invited talk.
Tau workshop - Is tau a prion-like protein? Implications for physiology and pathology. Madrid October 2013. Invited talk.