2004 Investigator-Initiated Research Grant

A key pathological feature of Alzheimer’s disease and some related disorders is an abnormal structure in cells called a neurofibrillary tangle. The main component of a tangle is a protein called tau, which plays an important role in maintaining the structure and stability of cells. The development of tangles appears to be closely associated with the degeneration of cells.

It is normal for the chemical properties of tau to be altered with the addition of phosphate groups. The tau proteins found in neurofibrillary tangles, however, have had unusually high levels of phosphate groups added. These hyperphosphorylated tau molecules are abnormally shaped.

The enzymes responsible for phosphorylation are called kinases. One potential treatment strategy to stop or slow the degeneration of cells is to inhibit the work of kinases, thereby preventing hyperphosphorylation. Karen Duff, Ph.D., and her colleagues are assessing the effect of two experimental compounds, each of which inhibits a different kinase.

The studies will be conducted with genetically engineered mice that develop pathological features of Alzheimer’s disease, including neurofibrillary tangles. The investigators will compare the effect of the two compounds administered at three different stages of disease development, examine how the kinases and tau function after kinase inhibition, assess changes in kinase interactions with other proteins, and determine how altered phosphorylation affects the properties of tau and the formation of tangles. The studies in animal models may provide valuable information about the utility of kinase inhibitors to treat Alzheimer’s disease and related disorders.