Structure-Function and Biochemical Analysis of Tau

One of the major disease related features of the brains of people with Alzheimer’s Disease is neurofibrillary tangles. Neurofibrillary tangles are insoluble aggregates that fill Alzheimer’s neurons, and are almost entirely of a single protein called tau. Tau is a protein that is produced in healthy brains where it is involved in the regulation of the architecture of nerve cells by interacting with another protein known as tubulin. Somehow tau’s structure becomes altered in Alzheimer’s disease. Abnormal tau interacts differently with tubulin, and tau becomes a major contributor if not the cause of pathology in Alzheimer’s disease by forming NFTs. We will use techniques of molecular biology and X-ray crystallography to learn more about the differences between normal and abnormal tau. We can divide the tau protein into functional pieces that we can study separately. With X-ray crystallography we can determine what these pieces look like in both their normal and abnormal forms. To do this we must crystallize the tau fragments, which is the major work we propose to do with research funds from the AHAF. We will also look more closely at the interaction between tau and tubulin in order to determine the best way to proceed with the study by crystallography of the tau – tubulin interaction. We hope that knowing what tau looks like will give us ideas about how to inhibit the change from the normal to the diseased state.