Targeting Brain Immune Cells as a Novel Therapeutic in Alzheimer's Disease

The project aim is to understand how a brain immune cell protein and novel therapy target offer protection against Alzheimer’s disease.

Microglia are immune cells in the brain with an increasingly recognized role in Alzheimer’s disease. Carla Rothlin, PhD, and her group have identified a microglial protein that seems to protect cells against the effects of Alzheimer’s disease. Increased activity of the protein, called AXL, is linked to protection against cognitive decline in lab models of Alzheimer’s disease.

Dr. Rothlin and her team hope to determine exactly what AXL does that offers this protection. Possibilities based on the known functions of AXL include a role in clearing out dead cells or amyloid-beta plaques that mark the condition or in preventing brain inflammation associated with Alzheimer’s disease.

To follow the process that leads to this protection, the team plans to use a series of lab models, each with one AXL function selectively disabled while retaining the others. In this way, Dr. Rothlin’s group will sort out which AXL function offers protection against Alzheimer’s disease and follow the sequence of events that leads up to more AXL production by microglia.

AXL is a promising lead in part because drugs, including antibodies that target this class of proteins, have been being developed for many years. In addition, a natural molecule that activates AXL, known as GAS6, has already been identified, giving researchers a head start on finding ways to trigger AXL activity. The researchers expect the findings to highlight targets for such treatments that could modify or protect against Alzheimer’s disease.

Our proposal involves a new target in a cell type that is not typically considered as a drug discovery target in Alzheimer’s disease. While there is exciting new data on microglial protection against AD, and a single drug discovery trial from a pharma company to the best of our knowledge, the concept is still unusual and against the grain of the prevalent Abeta-targeting approach. We also propose the use of innovative and heretofore unknown mouse models of loss of specific aspects of AXL function.

We propose a new microglial target in Alzheimer’s Disease – AXL. AXL belongs to the receptor tyrosine kinase family, a tractable pharmacological target studied for 50 years. Antibodies can be generated to activate RTKs. Additionally, a natural agonist for AXL is also well-known – GAS6. Thus, our research will be a step towards a potential treatment for Alzheimer’s Disease by revealing molecular mechanisms crucial for protection and the identification of a new drug discovery target.