Caspase-2-mediated tau cleavage at aspartate-314 has a broad impact on multiple types of dementia. This project investigates how this tau cleavage affects neurodegeneration in frontotemporal dementia. Preliminary data show that this site-specific tau cleavage promotes neurodegeneration and expression of genes associated with senescence and apoptosis. Importantly, previous findings from other groups show that senescence markers mediate tau-induced neuropathology and cognitive dysfunction. Therefore, the hypothesis is that this tau cleavage event mediates neurodegeneration through the senescence/apoptosis pathway. Using genetically matched mice which express either caspase-2-sensitive or caspase-2-resistant human tau transgenes, the researchers plan to compare gene expression profiles of the two lines and identify genes that are significantly altered. Successful completion of this project will further understanding of the mechanisms of this cleavage event on tau-associated pathology.