We know that Alzheimer’s disease is caused by the clumping together of misfolded proteins in the brain, specifically two proteins called amyloid beta and tau. We know that new antibody treatments for Alzheimer’s disease target the surface of clumps of amyloid beta and remove the clumps from the brain. Unfortunately, these drugs have significant side effects such as brain swelling and bleeding and don’t stop the disease. How can we improve on these treatments?

We believe the drugs don’t work well because they are targeting the surface of the wrong shape of clumped protein. Many different proteins can form clumps of different sizes and shapes in the brain during dementia, but only some of these are responsible for the disease. We plan to identify all the potential disease-causing protein clumps as they exist in the brain, then use this information to suggest new targets for drug therapy.

Previous studies of protein clumps rely on first purifying them from brain. Unfortunately, this step can change their shape and surface. We will avoid this by applying a paint-like coating to the clumps before purification. This will mark all the surface parts of the proteins. Then we can purify and analyze all the clumps to determine what the starting clumps looked like, based on which surfaces are painted, like reassembling a jigsaw puzzle.

The goal is to identify the most relevant protein targets for therapy. We have drugs that can remove protein clumps from the brain successfully, but currently they have significant side effects and don’t stop the disease. By capturing the full range of clumps that are actually in the brain before purification, we may find more relevant protein targets for the creation of more effective therapy with fewer side effects.

For so long we have had no therapies to offer that can actually stop the disease. We are now in a new era of drugs that can get rid of the clumps of protein that we think cause the disease. This is generating tremendous hope that a cure is around the corner. We just need to define exactly which clumps of protein are the most relevant to target. This project aims to do just that.