Microglial Protein Signatures in Progressive Supranuclear Palsy

Pathway Grant

Annelies Quaegebeur, University of Cambridge

The brain has its own specialised immune system, separate from the rest of the body. A key part of this system are microglia, immune cells that help maintain brain health by clearing debris, supporting nerve cells, and responding to injury. However, when abnormal or “junk” proteins build up in the brain, microglia can become overactive and start to cause damage instead of protection.
In the illness called Progressive Supranuclear Palsy (PSP), one such abnormal protein is tau. The build-up of tau in brain cells is closely linked to inflammation, which worsens brain damage over time. Much of what we currently know about microglia comes from studies using cells grown in dishes or from rodent models. However, microglia in humans differ significantly from those in animals - not only in their genetic activity (RNA) but also likely in their proteins, which are the molecules that actually perform most cell functions. This gap in knowledge about human microglia limits our ability to understand how these cells contribute to diseases like PSP and how they could be targeted for treatment.

Our project will investigate microglia directly in human brain tissue donated by people with PSP. We will study the protein “fingerprints” of microglia - the specific sets of proteins they express - and how these differ across brain regions and disease stages. Using advanced imaging techniques, we will measure and map a wide range of microglial proteins within the brain, and examine how these patterns relate to tau accumulation and damage to nearby nerve cells.

By focusing on proteins rather than genetic activity and using human brain samples instead of rodent models, our research will provide new insights into how microglia change in human tau disorders. The findings may help identify new and more specific biomarkers and potential therapeutic targets to slow or prevent brain damage.