Valproic Acid Stimulates Hippocampal Neurogenesis via Activating the Wnt/β-Catenin Signaling Pathway in the APP/PS1/Nestin-GFP Triple Transgenic Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by the deposition of amyloid-beta (A beta) peptides and neurofibrillary tangles (NFTs) and massive loss of neuronal cells in the brain. Adult hippocampus continuously generates new neurons throughout life to shape brain function and impaired neurogenesis may contribute to a series of cognitive deterioration associated with AD. Enhancing endogenous neurogenesis represents a promising strategy that may ameliorate AD-associated cognitive defects. However, neurogenesis-enhancing approaches and underlying mechanisms are still not well studied. Here, using a mouse model of AD amyloid precursor protein (APP/PS1/Nestin-GFP triple transgenic mice, 3xTgAD), we examined the effects of 4 weeks of valproic acid (VPA) treatment on hippocampal neurogenesis in 2- and 6-month-old mice. VPA treatment promoted cell proliferation and increased the density of immature neurons in the dentate gyrus (DG) of the hippocampus of 3xTgAD mice. Consistent with enhanced neurogenesis, behavioral and morphological analysis showed that VPA treatment improved the learning and memory ability of 3xTgAD mice. Mechanistically, VPA treatment increased beta-catenin levels, accumulated the inactive form of glycogen synthase kinase-3 beta (GSK-3 beta), and induced the expression of NeuroD1, a Wnt target gene involved in neurogenesis, suggesting the activation of the Wnt signaling pathway in the hippocampus of 3xTgAD mice. This study indicates that VPA stimulates neurogenesis in the adult hippocampus of AD mice model through the Wnt pathway, highlighting VPA as a potential therapeutic for treating AD and related diseases.