Diabetes is a risk factor for Alzheimer's disease. We tested the effects of Val(8)GLP-1, an enzyme-resistant analogue of the incretin hormone glucagon-like peptide 1 originally developed to treat diabetes in a mouse model of Alzheimer's disease that expresses mutated amyloid precursor protein (APP) and presenilin-1. We tested long term potentiation (LTP) of synaptic plasticity, inflammation response, and plaque formation. Val(8)GLP-1 crosses the blood-brain barrier when administered via intraperitoneal injection. Val(8)GLP-1 protected LTP in 9- and 18-month-old Alzheimer's disease mice when given for 3 weeks at 25 nmol/kg intraperitoneally. LTP was also enhanced in 18-month-old wild type mice, indicating that Val(8)GLP-1 also ameliorates age-related synaptic degenerative processes. Paired-pulse facilitation was also enhanced. The number of beta-amyloid plaques and microglia activation in the cortex increased with age but was not reduced by Val(8)GLP-1. In 18-month-old mice, however, the number of Congo red positive dense-core amyloid plaques was reduced. Treatment with Val(8)GLP-1 might prevent or delay neurodegenerative processes.