Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the tauopathies. To define the molecular mechanisms controlling tau-induced neurodegeneration we (Dr. Gamblin) have performed extensive biochemical characterization of tau variants, including splicing isoforms and mutants linked to the familial tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17. Importantly, these biochemical studies have defined tau variants with altered aggregation and microtubule binding properties. In parallel we (Dr. Feany) have created Drosophila models of tauopathy. Our models recapitulate key features of the human diseases, including age-dependent neurodegeneration, abnormal tau phosphorylation, aggregation of tau into fibrillary tangle-like inclusions, and early death. We will now combine our strengths in biochemistry and in vivo tauopathy modeling to define the species of tau that cause cellular and organismal toxicity in tauopathies. PUBLIC HEALTH RELEVANCE: The proposed studies will combine the mechanistic strengths of biochemical studies with the use of fruit flies as a fast, cheap model system to pinpoint the form of tau that causes neurons to stop functioning normally and eventually die. These studies will help us design better therapies for Alzheimer's disease and related neurodegenerative disorders.