Half of our lab is interested in mapping the changes that occur in the tau molecule during the progression of Alzheimer's Disease and other related neurodegenerative disorders. We feel that this is important since tau forms insoluble aggregates in the brains of people that are afflicted with these diseases. It has been shown that the appearance of these pathological structures of tau correlate with the degree of dementia. Secondly, tau pathology can be found in neurodegenerative disorders in the absence of any other major pathological structures. Lastly, tau polymerization has been shown to be sufficient to cause neurodegeneration and neuron loss in a non-mammalian animal model. Therefore, although other pathological structures could be involved in the neurodegeneration in Alzheimer's disease, we feel that the polymerization of the tau molecule is a very important step that leads to neuron dysfunction and loss.
It would be beneficial, then, if we could find a way to block tau polymerization from occuring in the brain. In order to do this, we must better understand what causes tau to polymerize. If we can understand that, then it might be possible to design drugs that would interfere with the process. We are approaching this problem by trying to model tau polymerization in a test tube. We use human tau protein that has been cloned and expressed in bacteria for these studies. We have developed an assay that allows us to measure tau polymerization efficiently, and we use that assay to model disease-associated alterations in the tau molecule that effect filament formation.
The changes we have modeled to date include: