2022 Alzheimer's Association Research Fellowship (AARF)

Single Domain Antibody-Based Protein Degrader Targeting Alzheimer's Disease

Can you impact the immune system to help clear tau protein to improve behavior in a model system of Alzheimer’s?
 

Yixiang Jiang, 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. Most of these studies involve whole antibodies, but smaller antibody fragments (known as single domain antibodies) may work better within the brain and inside brain cells. However, there have been few studies of the efficacy of such therapies.

Research Plan

Dr. Yixiang Jiang and colleagues have developed fifty-one (51) antibodies against the tau protein and have been able to demonstrate these antibodies are able to enter the brain. As a next step, the researchers will evaluate each of these compounds for ability to degrade tau in brain cells; these brain cells are grown in laboratory dishes from genetically engineered Alzheimer’s-like mice. The team will study which compounds are effective in both nerve cells and other brain cells, such as immune and support cells. The team will also study the best-performing of these antibodies by injecting them into genetically engineered Alzheimer’s-like mice. Dr. Jiang and team will investigate the potential functional benefits of the treatment using behavioral tests. The researchers will also assess levels of tau, brain inflammation and immune activity in the mice.

Impact

If successful, the results may highlight the potential benefits of smaller, more potent anti-tau antibodies in brain diseases involving the accumulation of tau, including Alzheimer’s. The findings may contribute to our understanding of the biology of such diseases and contribute to work that advances new avenues for therapies.