Does failed waste removal explain tau’s role in dementia?

Lead Investigator: Professor Diane Hanger

• Institution: King’s College London
• Grant type: Project
• Duration: 36 months
• Amount: £263,857

Why did we fund this research?

Comments from our Research Network volunteers:
 

Positive results will be a big step in enabling the development of new therapies.

Project summary

The build-up of the protein tau into tangles is one of the main underlying causes of dementia, but it remains unclear exactly how tau tangles causes brain cells to die.

This research team want to to find out whether tau kills nerve cells by preventing their waste removal systems from working properly, causing unwanted material to build up and damage the cell. 

If successful, this research team could identify a new way to block the negative effect of tau tangles, allowing us to develop treatments to prevent dementia from progressing. 

The background 

The build-up of the protein tau into tangles is understood to be one of the main underlying causes of dementia. But we still don’t understand exactly why tau causes nerve cells to die and ultimately lead to the symptoms of dementia.  

Professor Hanger and her team have identified a shortened fragment of tau, called Tau35, which has been found in the brains of people with dementia. Previous studies have shown that cells genetically engineered to produce Tau35 develop problems with part of the cells called lysosomes. Lysosomes are compartments within cells that help to break down unwanted and damaged proteins. 

The researchers think that Tau35 might prevent lysosomes from working, meaning they aren’t able to remove waste from nerve cells properly. This leads to unwanted proteins building up and damaging the cell. The research team want to find out how Tau35 interferes with this waste removal system so that they can better understand the steps in the process that lead tau tangles to cause the death of nerve cells in dementia. 

What does this project involve?

Professor Hanger and her team have genetically engineered mice to produce Tau35. These mice develop symptoms like those of dementia, including memory problems and tangles of the tau protein in the brain. The researchers will grow nerve cells from these mice in the lab and compare them to nerve cells taken from healthy mice to see if Tau35 affects lysosome numbers, appearance or function.

The researchers will then see if there are problems with how lysosomes are made. The protein TFEB controls the production of lysosomes.  They will label TFEB in Tau35 nerve cells with a dye and look at it under the microscope to see where it is located and if this is changed when Tau35 is present. They will then treat the cells with molecules that activate TFEB to see if this is able to block the loss of lysosomes and restore nerve cells’ normal function. 

How will this project help people with dementia?

The build-up of tau protein into tangles is one of the processes thought to cause nerve cell death and the symptoms of dementia. But researchers don’t yet know how exactly tangles form in the brain or how tangles damage nerve cells, leading to their death.  

If Professor Hanger and her team can discover the process through which Tau35 damages nerve cells, they may be able to design treatments that block this process and prevent nerve cell death and symptoms of dementia developing.