A major goal of the lab is to advance our understanding of the role of tau in neurological disease. We are motivated by the fact that tau is a causal or contributing factor in a broad range of neurodegenerative diseases that lead to dementia. Prominent among these diseases are the inherited tauopathies known as FTDP-17s (Frontotemporal Dementia and Parkinsonism linked to chromosome 17). These are the result of autosomal dominant mutations in the tau gene that affect its expression, its ability to bind to microtubules and/or its ability to form insoluble polymers in the cell. Intracellular tau aggregates form and, in some as yet undetermined fashion, lead to neuronal dysfunction and death. Insoluble tau aggregates are a hallmark pathology in Alzheimer’s disease (AD) as well, and it stands to reason that they lead to cellular dysfunction and death in this disease as they do in the tauopathies. In AD, however, the cause of tau polymerization is not a mutation in the tau gene. Rather it is suspected to be a phosphorylation, truncation, or conformational change in tau that is driven by the cell’s response to extracellular aggregates of the amyloid A-beta protein. Finally, there are some neurodegenerative dementias, such as Huntington’s disease, in which tau is not involved, and others, including multiple system atrophy, in which, while it is a participant in the pathology, it does not appear to be a major player.

We seek to establish the changes in tau phosphorylation, truncation, and conformation that occur in various neurodegenerative diseases in order to determine which of them might be responsible for driving tau polymerization. We do so by qualitative and quantitative immunohistochemistry using antibodies we and others have generated against tau in various states. We use both standard light microscopic techniques and double- and triple-label laser scanning confocal microscopy. We have begun to study the major tau-related neurodegenerative diseases and have characterized the cellular tau pathology in each of them.