Recent experimental work on synaptic plasticity mechanisms has uncovered a surprising result relevant to Alzheimer's disease (AD). This work has studied long-term potentiation (LTP), a synaptic change thought to underlie memory storage. LTP has two phases, an early phase that does not involve structural change and a later, persistent phase that does. This late LTP requires dopamine release in the hippocampus. Recent work has revealed that the required dopamine does not come from the classic dopamine releasing cells, but, unexpectedly, comes from the noradrenergic cells of the locus coeruleus (LC). This carries significance for Alzheimer's disease because of the long-standing demonstration that the LC is one of the first brain structures where degeneration occurs in AD. Thus, memory problems in AD could arise from loss of the LC axons, a consequent lack of dopamine release, and a resulting deficit in late LTP. It thus seems plausible that memory deficits in AD might be ameliorated by a process that enhanced dopamine release from the remaining LC axons. Moreover, because of evidence that LC lesions exacerbate the degenerative changes in AD, it is possible that enhancing dopamine release might reduce degenerative changes. We will test the hypothesis that release of dopamine from LC axons might be enhanced by blocking the enzyme dopamine-beta-hydoxylase (DBH) that converts dopamine to noradrenaline. Importantly, there are drugs appropriate for human use that block DBH and which might be repurposed for AD. In the proposed experiments, we will test whether these DBH inhibitors can enhance memory in an AD model and slow the degenerative process.