Project Summary/Abstract Alzheimer’s disease (AD) is significant health threat that is the fastest growing top 10 cause of death in the United States. AD currently costs Americans $280 billion dollars in direct health care costs annually. AD is characterized by, among other things, fibrils of aggregated microtubule associated protein tau. Tau in these fibrils is unique in several ways including truncation by caspases. The role of caspases and cleaved tau in AD has not been clearly defined, and two non-mutually exclusive hypotheses have been proposed. The first hypothesis is that caspases are being upregulated early in AD and cleave tau to a toxic species. A second possible explanation is that caspases are overexpressed in response to tau upregulation and cleavage of tau occurs after AD progression has been initiated. The overall goal of this proposal is understanding the role caspase cleaved tau plays in tau pathology. To date, several truncated tau products have been observed in vivo, but most efforts to understand the role of these products has revolved around genetic or chemical inhibition of caspases. Among all caspases, inhibition of caspase-3 and capase-6 have shown to alleviate tau pathology and cell death in cell and animal models. Knockout of caspase-3 is lethal in mice, but caspase-6 can be knocked out of mice without any adverse effects. This begs the question, is caspases-6 a potential therapeutic target for the treatment of AD? For the answer to this question to be yes, it must be shown why blocking caspase-6 alleviates tau pathology. Our central hypothesis is that caspase cleavage of tau results in a proteotoxic species that promotes tauopathy and cell death in AD. To demonstrate this, we will first characterize where caspases can cleave tau in a recombinant system. Next, we will characterize the stability, seeding propensity, cellular half-life, and toxicity of these cleaved tau proteins. Finally, we will show that cells expressing uncleavable tau are resistant to toxicity associated with caspase induction. These experiments will demonstrate that tau cleavage is necessary for neuronal cell death induced by caspase induction. When combined with previous the observations that 1) cleaved tau correlates with AD progression and 2) blockage of caspase activity alleviates tau pathology and cell death, the proposed research will provide a strong case for caspases as therapeutic targets in AD.

Project Narrative Patients with Alzheimer’s disease have plaques in their brains containing, among other things, caspase cleaved tau protein. The goal of this proposal is to characterize the role that caspase cleavage of tau plays in the progression of tau pathology. The outcome of these experiments will provide valuable insight into events happening early in the progression of Alzheimer’s disease as well as further validate caspases as targets for the development of treatments for the disease.