Caspase-Cleavage of Tau in Alzheimer's Disease

Direct, functional evidence for the involvement of caspases in driving AD pathology is currently lacking. The current proposal will test directly the role of caspases in AD by blocking caspase activation in an AD transgenic mouse model and examining whether such inhibition prevents the pathology associated with these animals.

Introduction: Recent studies have suggested that proteolytic cleavage of tau by caspases may be an important event linking beta-amyloid with neurofibrillary tangles in Alzheimer’s disease (AD). These studies suggest that caspase activation may play an important role in driving AD disease pathology and simply do not represent end-stage events associated with this disease. Hypothesis: Direct, functional evidence for the involvement of caspases in driving AD pathology is currently lacking. The current proposal will test directly the role of caspases in AD by blocking caspase activation in an AD transgenic mouse model and examining whether such inhibition prevents the pathology associated with these animals. Specific Aim 1: Crossing 3xTg-AD mice with Bcl-2 OE Tg mice will prevent the caspase cleavage of tau Specific Aim 2: Mice resulting from crossing 3xTg-AD mice with Bcl-2 OE Tg mice will exhibit fewer tangle alterations. Long-term goals: Direct evidence indicating a causative role for caspases in AD may stimulate the development of caspase inhibitors for their potential in treating this disease. In addition, results from this pilot study will provide the necessary feasibility and data for the development of a more comprehensive proposal examining all pathological aspects of these novel AD mice.