Acta Neuropathologica Communications: A new TAO kinase inhibitor reduces tau phosphorylation at sites associated with neurodegeneration in human tauopathies
Researchers in London have identified a promising approach for tackling the hallmark Alzheimer’s disease protein, tau. The findings of the research, which was funded by Alzheimer’s Research UK, are published today (Monday 7 May) in the scientific publication Acta Neuropathologica Communications.
One of the key hallmark features of Alzheimer’s is an abnormal build-up of a protein called tau in the brain, but there are several different neurodegenerative diseases that are caused by abnormal tau. Known collectively as tauopathies, these diseases affect hundreds of thousands of people in the UK.
In healthy nerve cells, tau protein plays an important role supporting the structure of the cell. In diseases like Alzheimer’s, tau becomes overloaded with chemical tags called phosphates, and strands of the protein stick together to form toxic tangles.
In this study, Dr Jonathan Morris and Prof Diane Hanger from King’s College London, zeroed in on molecules called thousand and one amino acid kinases or TAOKs. TAOKs number among several proteins that can regulate chemical reactions in which tau gets tagged with phosphates. The team set out to investigate whether TAOKs might be involved with the runaway addition of phosphate tags that scientists see in diseases like Alzheimer’s.
The researchers analysed brain tissues collected by the MRC London Neurodegenerative Disease Brain Bank, from people who died with either Alzheimer’s disease or frontotemporal dementia – two forms of dementia that involve the build-up of tau. They found evidence of abnormal TAOK activity alongside tau tangles in both cases, implicating these proteins in driving damaging disease processes.
The researchers studied the effect of blocking TAOK activity in nerve cells grown in the laboratory. Using stem cell techniques, they were able to grow human nerve cells that reproduced the processes that cause tauopathies in people. Using an experimental drug called Compound 43, the team reduced the activity of TAOK in cells and successfully lowered the amount of abnormal tau that the cells produced.
The research team is now working with experts from the Alzheimer’s Research UK Oxford Drug Discovery Institute to explore the findings further.
Dr Jonathan Morris, whose team led this study, has previously pioneered research into the role of TAOKs in the development of cancer. He said:
“Tau is a key player in a number of diseases that cause dementia, and an important target for future dementia treatments. These findings are at an early stage of development but highlight a potential new approach for tackling the build-up of tau and limiting the damage to nerve cells, which causes the devastating symptoms of dementia.
“We are now working with experts from the Alzheimer’s Research UK’s Oxford Drug Discovery Institute to further assess the potential of targeting TAOKs to treat diseases like Alzheimer’s, and to develop this work towards something that could help people with dementia.”
Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:
“It is fantastic that scientists like Dr Morris, who has a background in cancer research, is bringing his expertise to bear in dementia research. Dementia is now the leading cause of death in the UK, and there are no treatments that can tackle the diseases that cause the condition. In order to develop effective drugs sooner, it is vital that researchers come at these diseases from as many different angles as possible.”
“While this is early-stage research, the findings add to our understanding of a process involved in multiple brain diseases. We need to continue to invest in research in order to realise the potential of interesting findings like these.”
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