ROLE OF APP AND INTERACTING PROTEINS IN SYNAPTIC DAMAGE

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Alzheimer's disease (AD) is characterized by the presence of both beta-amyloid plaques and neurofibrillary tangles in brain. Increasing evidence favors the generation and deposition of amyloid beta-protein (Abeta) in senile plaques as an early and possibly primary event in the pathogenesis of AD. According to this "amyloid hypothesis", Abeta may first target the synapse, initially causing functional perturbations, followed by physical damage and synapse loss, and subsequently neuronal injury. The mechanisms and cellular pathways by which Abeta causes synapse loss and neuronal death are unclear. We have recently demonstrated in preliminary studies that Abeta can accelerate APP multimerization, an event that appears to increase the susceptibility to cell death. This pathway requires an intact APP cytoplasmic region, especially the caspase cleavage site near the C-terminus. These preliminary results have led to the working hypothesis that the APP cytoplasmic domain plays an important contributing role in synapse loss and neuronal death in AD. We propose a model in which one pathway of Abeta- induced cell death involves complex formation with APP, a model which has parallels to the well described FasL-Fas receptor pathway. Importantly, support of this model has been obtained from preliminary analyses of a newly generated line of APP transgenic mice in which the consensus caspase cleavage site in the APP cytosolic tail has been mutated (D664A) so that it cannot be cleaved. High levels of Abeta are generated in the brains of these animals together with Abeta deposits but there is no detectable loss of synapses as determined by synaptophysin immunoreactivity. Theses in vivo observations are entirely consistent with our model in which the synaptic damage in APP transgenic mice is mediated by a pathway that involves both Abeta and the APP cytoplasmic domain. In the first Specific Aim, our goal is to characterize in detail the morphological, electrophysiological, and behavioral phenotype of this newly generated APP D664A transgenic mouse line. In the second Specific Aim, we will initiate studies in human brain samples to correlate levels of caspase cleaved APP with premortem cognition and AD pathology. In addition, we will initiate studies to identify proteins that interact with APP in brain. In sum, results from these proposed experiments should provide important mechanistic insights into synapse loss in brain of AD individuals.