The goal of this study present study was to characterize the effects, of a clinically approved Type 2 diabetes drug, exendin-4 (Ex-4), an agonist of the of the glucagon-like peptide-1 receptor (GLP-1R), on stress-induced toxicity in neuronal cultures and on amyloid-β protein (Aβ) and tau levels in 3xTg-AD mouse model . 3xTg-AD mice were treated with streptozocin (STZ) to model diabetes. 3xTg-AD mice treated with saline instead of STZ served as controls. STZ 3xTg-AD mice were found to have elevated levels of APP and Aβ compared to saline treated mice. STZ treatment of Tg mice did not affect tau levels significantly. Compared to vehicle Ex-4 treatment ameliorated the diabetic effects of STZ in Tg mice, as measured by elevated plasma insulin and lowered plasma glucose and hemoglobin A1c (HbA1c) levels. In addition, Ex-4 treatment, compared to vehicle, ameliorated the STZ-induced increases in APP and Aβ. Ex-4 ameliorated the toxicity of Aβ and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. Together, these results suggest that Ex-4 may have potential in treating AD alone or in association with Type 2 diabetes.