2021 Alzheimer's Association Research Grant (AARG)

Gain of Function or Loss of Function? - The role of Tau in ADRDs

How does abnormal tau impact communication and transport in the brain cells in Alzheimer’s and other dementia?

Yuyu Song, M.D., Ph.D.
Massachusetts General Hospital
Boston, MA - United States

Background

Alzheimer’s and other neurodegenerative diseases, such as frontotemporal dementia and Pick’s disease, are characterized in part by the accumulation of an abnormal form of the tau protein. Tau is normally modified by a process called phosphorylation (or the addition of a molecule known as phosphate to specific parts on the tau protein). In Alzheimer’s and other brain diseases, the tau protein has too much phosphate added and this contributes to the tau clumping together and forming tangles. Tangles are a hallmark brain changes in these diseases. Though studies indicate that tau tangles may hinder brain cell function and could contribute to cell death, the mechanisms underlying these brain changes remain unclear. 

Studies suggest that tau is typically associated with microtubules, tube-shaped structures inside of cells that are crucial for maintaining cell shape and the shape of connections between brain cells. Dr. Yuyu Song and colleagues believe that a change happens to tau in Alzheimer’s and other dementias that causes it to dissociate from microtubules and alters its structure. This may result in abnormal tau that interferes with the nerve cell’s ability to transport materials between the cell body and a part of the nerve cell called the axon, a long, thread-like extension that helps nerve cells communicate. Dr. Song and colleagues suggest that problems in this cell machinery may lead to damage of these nerve cells, and ultimately may contribute to their death.
 

Research Plan

Dr. Song and team will study the impact of abnormal tau on the cell’s ability to transport between axons and nerve cell bodies, as well as how tau interacts with microtubules. The researchers will use advanced microscopy techniques to study tau in squid giant axons grown in the laboratory. Next, they will study the impact and interaction of tau in nerve cells created from a special kind of stem cell from mice called induced pluripotent stem cells, as well as in nerve cells from genetically engineered Alzheimer’s-like mice.

Impact

The results of this project may shed light on the role that the structure and function of tau plays in health and disease. If successful, the findings may lead to a better understanding of the biological underpinnings in these brain disease, as well as identify new drug targets and biomarkers for Alzheimer’s and other dementias.