Targeting Caspase-2 in Alzheimer's Disease

Project Summary: Research published over the past 15 years has pointed to a critical role of the enzyme Caspase 2 in Alzheimer's disease (AD). Transgenic animals carrying human Amyloid Precursor Protein (APP) genes develop extensive amyloid plaques and show increasing memory impairment and synaptic loss. When Caspase 2 is removed from these animals, the amyloid plaques develop but the synaptic loss and memory impairment do not occur. Cell culture work has demonstrated that Caspase 2 is necessary of A? induced synaptic dysfunction and cell death. These results taken together with the observation that Caspase 2 activity is increased in human AD suggest that Caspase 2 is a potential therapeutic target for AD treatment. Caspase 2 is present at very low levels in the adult brain and increases only in disease or in the AD models suggesting that its inhibition might not affect normal cellular processes. The major obstacle to exploring this avenue of treatment has been the non-specificity of caspase inhibitors. In the work proposed here we will use two highly specific methods of inhibiting Caspase 2. The first uses a cell permeable form of siRNA to diminish the amount of Caspase 2 in the brain while the second uses a newly developed agent, RAIDDpep, which blocks the activation of Caspase 2. These agents will be tested for their ability to block the cognitive and synaptic effects of A? in the J20 APP transgenic mouse and in mice where A? is introduced acutely by stereotaxic injection. The results of this work have the potential to open a new avenue for AD therapy.