2023 Alzheimer's Association Research Fellowship (AARF)
Tau as a Self-Antigen that Drives T Cell Immunity in Alzheimer's disease
How may tau promote the body’s own immune system to damage healthy brain cells in Alzheimer’s?
Hao Hu, Ph.D.
Washington University, School of Medicine
Saint Louis, MO - United States
Background
As people age, the immune system (which the body and the brain uses to protect itself from disease) can become dysfunctional and promote the brain inflammation that leads to Alzheimer’s. In recent years, scientists have observed that immune system dysfunction may also play a role in another dementia-related process – the damage to brain cells by abnormal tau protein. Tau is a protein that normally functions to transport nutrients and help nerve cells maintain their proper structure. However, his abnormal type of tau, which becomes modified or “misfolded,” tends to clump together into tangles (a hallmark brain change in Alzheimer’s), and it may hinder cell-to-cell communication and promote brain cell death.
In studies with genetically engineered mice that develop misfolded tau, Dr. Hao Hu and colleagues found high levels of certain immune cells (called T cells) around tau tangles in the brain. T cells normally circulate in the body and help recognize foreign or potentially harmful molecules, which are called antigens. The researchers also found that by reducing tau-related T cell levels in the mice, they could block tau-related brain cell death. Taken together, these findings suggest that misfolded tau may promote Alzheimer’s by triggering the immune system to attack healthy brain cells – a process called an autoimmune response.
Research Plan
Dr. Hu and colleagues will expand on their earlier results. Using brain cells from older Alzheimer’s-like mice, they will identify which specific T cells become activated by recognizing tau molecules as antigens. They will also identify specific regions of the tau molecule that interact with these T cells. Next, the researchers will inject tau-interacting T cells into living mice and assess whether these immune cells increase brain cell damage and death in the animals.
Impact
Results from this study could help improve our knowledge of how the immune system can promote Alzheimer’s and other dementias. They may also lead to novel Alzheimer’s therapies that target tau-related T cells.