Developing novel screening strategies to identify modulators of microglial cell states

Summary

Microglial cells act like the immune system guards of the brain, and they’re closely connected to how Alzheimer’s disease develops. We hope to find new pathways of communication within these cells to discover ways to use existing drugs to control these pathways and help develop effective treatments for people with Alzheimer’s disease.

What are we doing?

The way microglial cells in the brain react and respond plays an important part in how late-onset Alzheimer’s disease (LOAD) develops. At least a quarter of the genetic risk variants for this type of Alzheimer’s are linked to genes found in microglial cells. Whilst there is extensive research into the underlying molecular reasons behind these genetic factors, there is limited  research into how we can use the abnormal behaviors of microglia caused by these genetic variants to find new treatments.

We aim to:

• generate high quality transcriptomic profiles of microglia harbouring Alzheimer’s disease risk variants known to alter cellular functions.
• use bioinformatic techniques to identify pathways and gene networks altered when harbouring risk variants
• identify drug treatments that induce similar profiles and gene networks to control lines and opposing profiles and gene networks to risk variant lines
• test candidates in phenotypic assays
• take positive candidates forward to pre-clinical studies

How are we doing it?

We’re going to derive microglia from human induced pluripotent stem cells (iPSC) to help us understand exactly how having certain genetic risk factors affects the behaviour of these cells.

We’ll analyse the genes in these cells to find out which pathways are affected the most. Then, we’ll compare our findings with existing databases to see if any drugs might be able to target these pathways.

Next, we’ll test these drugs in experiments to see if they have the desired effects on the cells. If they look promising, we’ll try them out on samples from real patients. Our aim is to find potential treatments quickly and bring them to patients.

What happens next?

We’ll gather data about how genes are controlled, specifically looking at gene methylation, which can affect how microglial cells become activated in Alzheimer’s disease. This will help us confirm the pathways and gene networks to target with new treatments.

Collaborators

Professor Katie Lunnon

Professor Soojin Ryu