Current Research Description

This laboratory investigates pathogenic pathways that lead to the appearance of granulovacuolar and neurofibrillary lesions found in Alzheimer's disease and other dementias. Three principal projects focusing on these hallmark intracellular lesions are underway:

1. We have developed a novel method for assembling filaments like those found in neurofibrillary tangles in vitro. The goals of this project are to characterize the mechanism of filament assembly, determine the contribution of postranslational modification in the process, and clarify the role of filament formation in neuronal cell death.
2. The second project focuses on protein kinases associated with granulovacuolar and neurofibrillary lesions of Alzheimer's brains, and seeks to determine the function of these enzymes in normal cell biology and in disease. In so doing, we hope to dissect the signal transduction pathways involved in AD pathogenesis. Because these phosphotransferases can also serve as robust markers for AD lesions in tissue, we are using them to map the spatial and temporal development of AD pathology, and to extend our observations to other neurodegenerative diseases.
3. The final project applies the techniques of X-ray crystallography and molecular modeling to assist in the rationale design of ligands suitable for whole-brain imaging of disease-associated markers. Overall, we hope to identify targets and develop ligands that are useful for pre-mortem diagnosis of and therapeutic intervention in neurodegenerative disease.