2004 Investigator-Initiated Research Grant

Tau is a protein that stabilizes a nerve cell’s transport system. It is normal for chemical properties of tau to be altered with the addition and subtraction of phosphate groups. These alterations help regulate its function inside the cell.

In Alzheimer’s disease and many related disorders, tau proteins gain unusually high levels of phosphate groups, and a portion of the protein is apparently sliced off. These altered tau proteins lose their ability to function normally and stick together in structures called neurofibrillary tangles.

Both the loss of tau function and the tangles themselves may contribute to nerve cell malfunction and death. Gail V.W. Johnson, Ph.D., and colleagues are investigating how these changes in tau contribute to disease processes.

The addition of phosphates, or phosphorylation, can occur at different sites along the tau protein. The researchers will test the hypothesis that phosphorylation only at certain sites alters tau’s interaction with the transport system and other tau proteins and that these distinct events have different effects on cell survival. They will also examine whether a tau protein cut by a specific enzyme at a certain site has a propensity to interact with other tau proteins and how such interactions influence cell survival.

The investigators will conduct their studies with genetically tweaked cells that enable them to examine these various factors in isolation. The results of this study may clarify the role of abnormal tau in Alzheimer’s disease and suggest targets for disease-modifying therapies.