Can a novel therapy using the body’s own immune system prevent brain diseases associated with tau protein?
Luc Buée, Ph.D.
Institut National de le Santé et de la Recherche Médicale
Tau is a protein that helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Brain diseases believed to result from the abnormal modification of tau are called “tauopathies”.
For many years, scientists have been working to create potential therapies for these tauopathies by targeting the tau protein itself. Some of these efforts employ the body’s own immune system to lower the accumulation of abnormal tau. Dr. Luc Buée and colleagues have been developing and testing “nanobodies” targeting tau. Nanobodies are fragments of antibodies that the immune system uses to recognize specific disease-causing molecules and mark them for removal. The researchers identified a nanobody that could target a specific segment of tau protein that promotes abnormal tau clumping. They found that this nanobody could prevent tau accumulation in brain cells grown in a laboratory dish and in genetically engineered Alzheimer’s-like mice.
Dr. Buée and colleagues will now conduct a larger study of nanobody-based therapies for tauopathies. First, they will take different variations of the identified nanobodies and combine them into double-nanobody structures called diabodies. Some of these diabodies will be designed to target the segment of tau known to promote tau clumping, while others will be designed to target another disease-related tau segment. Then, using brain cells grown in a laboratory dish, they will analyze the diabodies’ structure, examine how they bind to tau segments, and compare how well they prevent tau accumulation in the cells. Next, the researchers will test some of these diabodies in genetically engineered Alzheimer’s-like mice. Dr. Buée’s team will assess how well the diabodies prevent both tau accumulation and memory loss in the animals.
Based on results from these experiments, the investigators will identify a single diabody that best prevents tau-related brain damage. This will then be tested again in living mice to determine whether it may cause unwanted side-effects over time in the animals.
Dr. Buée’s project will shed new light on how tau accumulation takes place in brain disease. It may also identify a promising immunotherapy approach for tauopathies that could be tested in future human clinical trials.
The Tau Pipeline Enabling Program (T-PEP) is jointly funded by the Alzheimer's Association and Rainwater Charitable Foundation.
Back to Top