Synapses, the point of contact and communication between two neurons, are susceptible to damage by a pathological protein cleavage byproduct of the amyloid precursor protein (APP) called amyloid beta that accumulates in the brains of individuals who have Alzheimer’s disease. Specifically, synapses are removed, and the communication between the synapses that remains is weakened in part by the removal of a particular type of glutamate neurotransmitter receptors, called AMPA receptors. We discovered that a protein called NEDD4-1 is responsible for the degradation of AMPA receptors from synapses that facilitate normal learning and memory. We have shown that, in response to elevated amyloid beta levels, NEDD4-1 inappropriately eliminates AMPA receptors in cell culture models of AD; we intend to determine whether this holds true in mouse models. Furthermore, we find this appears to involve an aberrant signaling pathway involving PKCa previously known to operate downstream of amyloid beta to negatively affect synapses. We have proposed innovative strategies to uncover the functional relationship between NEDD4-1 and PKCa in AD. Many therapeutic strategies for AD are focused on reducing amyloid beta levels or by inactivating amyloid beta directly. However, identifying new molecules that mediate the pathogenic effects of amyloid beta is another area with significant promise. Thus, if achieved, our proposal would deliver NEDD4-1 as a new and potential therapeutic target to mitigate the effects of amyloid beta at synapses.