P1‐229: Effects of zinc plus cyclo(his‐pro) on pathology, learning and memory in a transgenic mouse model of Alzheimer's disease

Memory loss is a major clinical hallmark of Alzheimer's disease (AD), which currently affects over 26 million individuals worldwide. While the causes of AD are unknown, recent epidemiological studies show an increased risk of AD in both type 1 and type 2 diabetic patients. This may explain why mice given a high fat diet present with increased insulin resistance, enhanced amyloidosis and decreased levels of the zinc containing, Aβ metabolizing, insulin degrading enzyme (IDE). Previous work from our group shows that treatment with a novel patented formulation of zinc plus cyclo(his-pro), named ZC, significantly improves insulin sensitivity in several diabetic animals models. As AD may be linked to diabetes, we recently tested ZC's ability to alter Aβ levels, IDE activity, as well as learning and memory in a transgenic mouse model of AD. Nine to twelve month old huAPP-YAC transgenic mice (R1.40 strain) were treated with 10 mg/L Zn plus 1.0 mg/L cyclo(his-pro) in water ad libitum, with controls receiving access to water alone ad libitum. At the end of five weeks of treatment, Aβ levels and IDE activity were measured. Nine month old R1.40 mice, treated as previously described, were tested on a Barne's Maze for learning and memory at baseline and at monthly intervals. In this study we show that ZC decreases both cytosolic and membrane forms of Aβ1-42 and Aβ1-40, while enhancing IDE activity. Mice treated with ZC also show an increased ability to learn and remember the location of an escape hole. Here we demonstrate for the first time that a novel patented formulation decreases Aβ levels, increases IDE activity, and enhances learning and memory in an AD transgenic mouse model.