There is strong evidence suggesting that Alzheimer’s disease is caused in large part by the accumulation of a toxic protein termed A-beta (Aβ) in the brain. If scientists can understand in great molecular detail the very early steps of how Aβ accumulation impairs brain function, it will be possible to develop therapies that prevent these steps. One of the earliest effects of toxic forms of Aβ is to impair the ability of the connections between nerve cells, termed synapses, to modify their own properties in response to changes in the patterns of brain activity. This synaptic plasticity, in particular in a brain region termed the hippocampus, is thought to be critical for learning and memory and thus impairments in synaptic plasticity in the hippocampus likely account for many of the early and late symptoms of Alzheimer’s. While some of the molecular mechanisms underlying synaptic plasticity in the hippocampus have been elucidated, much is not known. My laboratory has developed novel approaches to the study of one form of synaptic plasticity, termed long-term potentiation (LTP), which seems to be particularly important in Alzheimer’s disease in that toxic forms of Aβ inhibit the mechanisms normally responsible for this plasticity. This impairment of LTP likely contributes to the cognitive impairment in early stages of Alzheimer’s disease as well as the eventual physical shrinkage and eventual loss of synapses. This research project will use sophisticated molecular, electrophysiological and imaging techniques to further elucidate the detailed molecular mechanisms of LTP in the hippocampus focusing on two proteins that have been genetically or biochemically associated with Alzheimer’s. We will molecularly manipulate these different synaptic proteins in individual nerve cells and define their specific roles in LTP. Importantly, we will express mutated versions of these proteins and determine if this prevents the detrimental effect of toxic species of Aβ on synaptic function and plasticity. The results of these experiments will provide novel proteins and mechanisms that can be targeted for treating Alzheimer’s disease by preventing the very changes in the brain that lead to its devastating symptoms.