MA-[d-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Mirrors the Cognitive Enhancing Action of Leptin in a Mouse Model of Type 1 Diabetes Mellitus and Alzheimer's Disease-Like Cognitive Impairment

Disruption of insulin signaling and glucose dysregulation in the brain have been suggested as a possible etiology of Alzheimer's Disease (AD), also known as type 3 diabetes mellitus. Increasing evidence indicates that the hormone leptin, in addition to its roles in energy balance and glucose homeostasis, greatly influences hippocampal learning and memory. Leptin, however, has shown only limited clinical application due to its ability to promote autoimmune disease and oncogenesis. In the present study, we show that oral delivery of MA-[d-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, when given in combination with insulin to young male Swiss Webster mice rendered diabetic by intraperitoneal injection of streptozotocin (STZ), prevented insulin-induced body weight gain and enhanced the effects of insulin on fasting blood glucose. Novel object recognition testing indicated that insulin improved, but did not normalize, episodic memory in STZ-induced diabetic mice. When MA-[d-Leu -4]-OB3 was given in combination with insulin, the effect of insulin on cognitive function was amplified, and the time course for this improvement was significantly accelerated. The results of this study suggest that the insulin-sensitizing action of MA-[d-Leu-4]-OB3 may have application to the treatment of AD by slowing or preventing the progressive memory disruption associated with this disease.