Neurogenesis in the subgranular zone of the hippocampal dentate gyrus may act as an endogenous repair mechanism in Alzheimer's disease (AD), and the Wnt signaling pathway has been suggested to closely modulate neurogenesis in amyloid-b (Ab)-related AD models. The present study investigated whether mesenchymal stem cells (MSCs) would modulate hippocampal neurogenesis via modulation of the Wnt signaling pathway in a model of AD. In Ab-treated neuronal progenitor cells (NPCs), the coculture with MSCs increased significantly the expression of Ki-67, GFAP, SOX2, nestin, and HuD compared to Ab treatment alone. In addition, MSC treatment in Ab-treated NPCs enhanced the expression of b-catenin and Ngn1 compared to Ab treatment alone. MSC treatment in Ab-treated animals significantly increased the number of BrdU-ir cells in the hippocampus at 2 and 4 weeks compared to Ab treatment alone. In addition, quantitative analysis showed that the number of BrdU and HuD double-positive cells in the dentate gyrus was significantly higher in the MSC-treated group than in controls or after Ab treatment alone. These results demonstrate that MSC administration significantly augments hippocampal neurogenesis and enhances the differentiation of NPCs into mature neurons in AD models by augmenting the Wnt signaling pathway. The use of MSCs to modulate endogenous adult neurogenesis may have a significant impact on future strategies for AD treatment.