Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) 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 β-catenin levels, accumulated the inactive form of glycogen synthase kinase-3β (GSK-3β), 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.
Highlights
Alzheimer’s disease (AD) is the most common form of age-associated dementia and shows increasing prevalence because of progressive aging of the population (Prince et al, 2016)
Numerous studies have indicated that changes in hippocampal neurogenesis in AD contribute to the plasticity of the hippocampus and to some hippocampal processes, including spatial learning and memory (Becker et al, 2007; Deng et al, 2010; Lazarov et al, 2010)
Studies have found that valproic acid (VPA), an anti-epileptic drug applied in the clinic, can relieve the pathological features of AD to a certain degree (Williams et al, 2002; Tariot et al, 2011; Wang et al, 2014)
Summary
Alzheimer’s disease (AD) is the most common form of age-associated dementia and shows increasing prevalence because of progressive aging of the population (Prince et al, 2016). It is characterized by multiple neuropathological features, such as the amyloid-β (Aβ) peptides aggregated into senile plaques (SPs), hyperphosphorylation of tau formed in the neurofibrillary tangles (NFTs), massive synaptic and neuronal loss that gradually leads to memory loss and cognitive impairment. The hippocampus is characterized by the continuous generation of new neurons throughout life (called adult hippocampal neurogenesis). A promising treatment avenue of AD is to promote neurogenesis in the affected tissue by stimulating NSCs and neural progenitor cells (NPCs) in the neurogenic niches
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