What is the role of microglia in frontotemporal dementia?

Research project: What role do microglia play in C9orf72-linked frontotemporal dementia?

Lead Investigator: Dr Sarah Ryan

  • Institution: University of Manchester
  • Grant type: Junior Fellowship
  • Duration: 36 months
  • Amount: £210,334

Why did we fund this research?

Comments from our Research Network volunteers:

If this project is successful it could lead to the first treatment for FTD (for the form related to the C9orf72 gene). And if an existing anti-inflammatory can be repurposed then length of clinical trials would be shortened.

Project summary

Frontotemporal dementia (FTD) is one of the most common types of dementia in people under 65. The major known cause of FTD is an error in a gene called C9orf72, but researchers don’t fully understand what leads this faulty gene to cause dementia symptoms. 

In this study, researchers will test whether proteins made by a faulty C9orf72 gene cause cells called microglia to become overactive and damage nerve cells. This knowledge will help scientists to design treatments that can slow or stop FTD. 

The background 

FTD is the second most common type of dementia in younger people, yet it is much less well studied than Alzheimer’s disease. The most common cause of FTD is a faulty gene called C9orf72. Researchers have discovered that the faulty C9orf72 gene makes abnormal proteins, which clump together inside the brains of people with FTD.

Recent research shows that these proteins can damage or kill nerve cells, that pass information around the brain and so may the cause of symptoms of dementia. But researchers don’t yet know exactly how abnormal C9orf72 proteins kill nerve cells. 

Like other forms of dementia, the brains of people with FTD show abnormally high levels of inflammation. Studies have shown that this excessive inflammation causes microglia, the brain’s resident immune cells, to become hyperactive and release substances that can damage the brain. Microglia can also eat away at the connections between neurons (synapses) preventing them from communicating properly and leading to the symptoms of dementia.

What does this project involve?

The researchers will grow mouse nerve cells found in the brain that produce the faulty C9orf72 proteins in a dish and then add microglia. This system allows the researchers to mimic what happens in the brain when microglia come into contact with C9orf72 proteins made by nerve cells with the faulty gene.

The team will examine whether microglia exposed to C9orf72 proteins damage nerve cells directly or in a more subtle way – by eating away at the connections between them.

One of the ways hyperactive microglia can damage nerve cells is by releasing chemicals called cytokines which activate the immune system , increasing inflammation in the brain. The researchers will analyse the liquid that the cells are grown in to find out which cytokines are being released by microglia exposed to the faulty C9orf72 proteins. 

The researchers also want to find out if these changes are seen in people. They will analyse brains donated by people with FTD caused by the faulty C9orf72 gene. Using microscopy and other methods, they will measure the levels of cytokines and other markers of inflammation in the brain and look at microglia to see how they are affected by C9orf72 protein clumps in nerve cells.  

How will this project help people with dementia?

This project will investigate how the faulty C9orf72 gene leads to the death of nerve cells in the brain and the symptoms of FTD. FTD is one of the most common types of dementia in people under 65, but researchers still don’t fully understand how it develops. 

Understanding whether microglia cause the inflammation seen in the brain of people with the faulty gene will help us design new treatments for FTD, and may even allow us to repurpose anti-inflammatory drugs already on the market. 
 

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