Tau protein builds up in the brains of people with Alzheimer's disease. Scientists have developed a drug that prevents this in experimental models of this disease. Among the scientists is Professor Amritpal Mudher, Professor of Neurosciences at Southampton.
Tau proteins play a crucial role in maintaining the structure and function of neurons or brain cells. In Alzheimer's disease, these Tau proteins stop working properly. They clump together and prevent the neurones from receiving the nutrients and signals they need to survive. As more neurons die, memory, thinking, and behaviour become increasingly impaired. This leads to the cognitive decline seen in Alzheimer鈥檚. There are two specific 鈥榟otspots鈥 of the Tau protein where this clumping tends to happen.
For the first time, we have a drug which is effective in inhibiting both these regions. This dual-targeting mechanism is significant because it addresses both domains that stimulate Tau aggregation, which could pave the way for more effective treatments for neurodegenerative diseases like Alzheimer鈥檚.
Professor Amritpal Mudher
The new drug, a peptide inhibitor called RI-AG03, was effective at preventing the build-up of Tau proteins in both laboratory tests and in studies using fruit flies.
Reduced side-effects
Another breakthrough is that this approach is more targeted than current treatments. This could potentially make it safer, with fewer side effects for patients.
鈥淚n drug research, scientists will identify a pathway or process in a cell that they deem to be toxic and then find a drug that blocks that pathway. This can be messy as a cell has many pathways and processes and the drug could end up having off-target effects,鈥 she explains.
鈥淭he beauty of our approach is that we looked at the pathogenic Tau protein itself and drilled down to the root cause of its toxicity. We played around genetically with deleting different parts of the protein, while still enabling it to function as it should. RI-AG03 was designed specifically against the Tau protein to mimic that genetic deletion.鈥
Amrit鈥檚 research into genetic mimicking is also due to be submitted to a journal.
The fruit fly test
RI-AG03 was first developed by Dr Aggidis, in the laboratory of the late Professor David Allsop, using computational biology at Lancaster University, where it was tested in lab dishes.
To test its effectiveness in cells within a living organism, Amrit gave the drug to fruit flies that had pathogenic Tau. The drug blocked neurodegeneration and extended the lives of the flies by around two weeks. This is a significant extension considering the life span of the insects. 鈥淭he higher the dosage given, the greater the improvement we saw in the fruit fly鈥檚 lifespan,鈥 she says.
The initial research, published in , was undertaken by Southampton in collaboration with Lancaster University, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and UT Southwestern Medical Centre.
Ongoing research
The findings are very promising as 28 different countries covered this project. The next stage is to test RI-AG03 in rodents, before proceeding to clinical trials.
We are at a very good starting point and are keen to take the necessary steps to translate our finding. We have had interest from various organisations that want to make the leap from the bench to the bedside. We are gathering baseline data to provide evidence of success in mammalian systems required for further funding.
鈥淗owever, there are a lot of steps before it can go to clinic. If I had a wishing wand, I would use it to collaborate with a pharmaceutical company that would enable us to get there quicker,鈥 she concludes.
