2022 Alzheimer's Association Research Fellowship (AARF)

Restoring Neuronal Function by Tau Antibody in a Tauopathy Model

Can targeting the tau protein restore nerve cell function in genetically engineered Alzheimer’s-like mice?

Changyi Ji, Ph.D.
New York University School of Medicine
New York, NY - United States

Background

Tau is a protein that helps to 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 abnormal modification of the tau protein are referred to as “tauopathies” and this includes Alzheimer’s, frontotemporal dementia, Parkinson’s disease, and others. Tau tangles are associated and likely contribute to increased brain cell damage.

An active area of investigation are potential therapies that target the tau protein, including using an antibody or immunotherapy that would use the body’s own immune system to lower the accumulation of abnormal tau. 

Dr. Changyi Ji and colleagues used a mouse model of tauopathy to develop antibodies against tau; these are molecules the immune system uses to recognize specific disease-causing molecules and mark them for clearance. The researchers have demonstrated that these antibodies work against tau in mouse nerve cells grown in laboratory dishes and in genetically engineered Alzheimer’s-like mice. However, how the antibodies work against tau to restore nerve cell function in mice remains unknown.

Research Plan

Dr. Ji and team will study how different monoclonal antibodies (meaning the antibody has a single target) against tau impact other biology in genetically engineered Alzheimer’s-like mice. Specifically the research team will evaluate the impact of the tau immunotherapy on calcium activity; calcium is a key component of brain communication networks and an indicator of nerve cell health. The researchers will use a state-of-the-art brain scan technique, called in vivo two-photon calcium imaging, to measure the calcium activity inside living mice exposed to different tau antibodies to understand how these antibodies impact the cells’ function. The antibodies are designed to attach to modified tau and clear the tau from the cell.

Dr. Ji and colleagues will inject genetically engineered Alzheimer’s-like mice with a calcium “indicator” molecule. This will help the team directly observe nerve cell calcium activity in living and awake mice. The team will collect calcium activity data in each mouse before, and after, exposing them to the tau antibodies. After collecting the live calcium activity data, the researchers will collect brain tissue samples from the mice to further analyze the mechanisms that these monoclonal antibodies may impact brain cell function in these mice.

Impact

The results of this study may provide insights into how tau antibodies impact nerve cell activity and underlying biology. A better understanding of how these antibodies work could provide valuable insight into their use as potential therapies for brain diseases caused by abnormal tau.