ABSTRACT AD is characterized by a progressive loss of memories over time. This has been hypothesized to be due to a loss of long-term potentiation (LTP) and other learning and memory mechanisms in neurons affected during Alzheimer’s Disease (AD) pathogenesis, a result observed both in rodent AD models as well as humans1,2. Much like AD patients lose the ability to recall former memories, AD model rodents also show deficits in memory recall3,4. This is presumably due to a destabilization of existing memories, though this has not been directly examined. If we could stabilize plasticity against destabilization that occurs during AD pathogenesis, we could prolong the persistence of adaptive memories, thus substantially reducing the symptomatic burden of AD patients and their caregivers. As LTP is thought to be a molecular substrate of memories, loss of LTP should be shortly followed by a loss of associated behavioral memories. Indeed, evidence suggests that this is the case; we find that deterioration of LTP in the hippocampus in the 5xFAD rodent model starts at roughly 4-6 months of age, followed closely by the loss of previously established hippocampal memories3,4. In our funded NIH Director’s Innovator Award (DP2AG067666), we proposed to develop a suite of molecular methods to modulate plasticity in a spatiotemporally-defined fashion. These approaches are based on the elucidation of the molecular mechanism of the small peptide ZIP, which we have found to work through macropinocytosis, as ZIP’s behavioral effects could be blocked by prior administration of amiloride. Importantly, we showed that amiloride not only blocks ZIP- induced destabilization of LTP, but also natural processes that remove AMPAR receptors, such as are required for long-term depression (LTD)-induced behavioral extinction. This raises the possibility that our methods for plasticity modulation, including amiloride administration and molecularly-defined variants, could be used as a therapeutic strategy to prevent destabilization of LTP that occurs during AD pathogenesis. This in turn could slow the development of AD-associated cognitive and behavioral deficits. In this administrative supplement application, we will test the ability of our approaches to slow the AD-associated loss of contextual and auditory fear conditioning memories, as well as conditioned place preference memories. Contextual fear memories can be disrupted by modulating LTP in the hippocampus5,6, and we show in our preliminary data that auditory fear conditioning memories are stored in the basolateral amygdala (BLA), and conditioned place preference memories are stored in the nucleus accumbens (NAc). We show that injection of ZIP or the small cationic peptide TAT into the BLA or NAc eliminates the associated memory, and the effects of ZIP/TAT were blocked by prior amiloride infusion. Here we will test the maintenance of these three memories in the 5xFAD AD model mice at two different ages following 1 month of eit...