Understanding the early events that lead to brain cell death in Alzheimer’s disease

Research project: Investigating the role of tauopathy-induced activating transcription factor 3: a transcriptional hub to modulate neurodegeneration

Lead Investigator: Dr Katrin Deinhardt

  • Institution: University of Southampton  
  • Grant type: PhD studentship
  • Duration: 36 months 
  • Amount: £84,906.96

Why did we fund this research?

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I feel that it is these areas of research - particularly those that push past funded research a step further, are a priority to fund.

Project summary

Researchers believe that in early Alzheimer’s disease, a protein called tau builds up in the brain cells and forms tangles which ultimately make the brain cell sick and die. However, we don’t yet know what happens within the brain cell as these tau tangles develop.

The project will look at how brain cells respond to tau build up whilst they are still alive and only just starting to become sick. This information could lead to new targets for future dementia therapies, which might be able to protect brain cells and prevent them from dying. 

The background 

The brain is made up of a network of nerve cells which have a very special structure. Brain nerve cells work together, passing information from cell to cell to allow different areas of the brain to ‘speak’ to each other and co-ordinate different activities; such as how we move, think or speak. 

In Alzheimer’s disease, two different proteins in the brain become misfolded and clump together into structures called plaques and tangles. The plaques form from misfolded amyloid protein outside of the brain’s cells, and the tangles form from misfolded tau protein inside the brain’s cells.

The build up of these two proteins tend to form in the areas of the brain responsible for memory, learning and emotion.

As a result of these protein deposits, brain cells become sick and eventually die. Currently, little is known about what happens inside brain cells whilst these tau tangles, in particular, develop and whilst the cell is still alive. 

What does this project involve?

This project aims to understand how brain cells respond as these tau tangles start to develop, at the point where the brain cell is only starting to get sick. Previous research by this group of researchers has identified a ‘switch’ called ATF3 inside brain cells with the ability to turn certain genes inside the brain cell on or off. This ‘switch’ will determine how the brain cell responds to the tau tangle developing inside it.

The researchers want to find out what effect this ‘switch’ has on the brain cell, and whether it helps protect the brain cell from damage or causes it to die faster. 

The PhD student will look for this ATF3 ‘switch’ first in the brains of mice with Alzheimer’s disease and then in the donated post-mortem brains of people who have lived with Alzheimer’s disease. They will then look at living cells grown in a dish in the lab, to examine the affect of this ATF3 ‘switch’ in brains cells with and without the tau tangles. This will allow them to compare healthy brain cells against those affected by Alzheimer’s disease. 

How will this project help people with dementia?

At present, we know that Alzheimer’s disease causes brain cells to die and for the nerve cell networks in the brain to break down. There is currently no way to protect brain cells and prevent this from happening. We are still missing pieces of the jigsaw puzzle that tell us why brain cells die and how they respond early on to the development of the protein plaques and tangles that are characteristic of Alzheimer’s disease. 

This research aims to fill in one part of that jigsaw and give more information on what happens to the brain’s cells in early Alzheimer’s disease. By understanding what happens to brain cells when they are starting to become sick and still alive, we can identify new targets for future therapies, which might be able to prevent the cell from dying and therefore prevent the brain’s nerve cell network from breaking down in Alzheimer’s disease. 

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