AbstractBackgroundAmylin is a pancreatic amyloid protein, known to regulate glucose homeostasis and satiety through its ability to sensitize insulin and leptin. Importantly, the amylin receptor (AMYR) is expressed throughout the brain, including areas important in both cognition and Alzheimer’s disease (AD) pathology, like the hippocampus. We and others have previously shown that an analogue of amylin, Pramlintide (PRAM), reduces Aβ plaque burden and recuses hippocampal‐dependent cognitive decline in AD‐mouse models. However, the mechanisms underlying the therapeutic benefits of PRAM are not known.MethodAPP/PS1 mice were treated with PRAM, or saline, chronically via a subcutaneous pump for eight weeks. Additionally, a second subcutaneous pump connected to an ICV cannula delivered an AMYR antagonist, AC187 or aCSF during the last four weeks of peripheral treatment. Radial Arm Water Maze was performed at the end of study to measure spatial memory. Soluble‐Aβ1‐42 hippocampal levels were measured via ELISA and APP processing enzymes were evaluated by Western Blot.ResultPreliminary data suggests central blockade of amylin receptors may exacerbate Aβ burden and prevent learning of spatial‐memory tasks; while PRAM treatment showed increased protein expression of certain Aβ degradation enzymes.ConclusionEvaluation of AMYR blockade in AD‐modeled mice has supported a deeper knowledge of amylin signaling in the brain.