Alzheimer's disease (AD) is a neurodegenerative disorder characterized by loss of memory and cognitive abilities, and the appearance of amyloid plaques composed of the amyloid-β peptide (Aβ) and neurofibrillary tangles formed of tau protein. It has been suggested that exercise might ameliorate the disease; here, we evaluated the effect of voluntary running on several aspects of AD including amyloid deposition, tau phosphorylation, inflammatory reaction, neurogenesis and spatial memory in the double transgenic APPswe/PS1ΔE9 mouse model of AD. We report that voluntary wheel running for 10 weeks decreased Aβ burden, Thioflavin-S-positive plaques and Aβ oligomers in the hippocampus. In addition, runner APPswe/PS1ΔE9 mice showed fewer phosphorylated tau protein and decreased astrogliosis evidenced by lower staining of GFAP. Further, runner APPswe/PS1ΔE9 mice showed increased number of neurons in the hippocampus and exhibited increased cell proliferation and generation of cells positive for the immature neuronal protein doublecortin, indicating that running increased neurogenesis. Finally, runner APPswe/PS1ΔE9 mice showed improved spatial memory performance in the Morris water maze. Altogether, our findings indicate that in APPswe/PS1ΔE9 mice, voluntary running reduced all the neuropathological hallmarks of AD studied, reduced neuronal loss, increased hippocampal neurogenesis and reduced spatial memory loss. These findings support that voluntary exercise might have therapeutic value on AD.

Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. This process is highly regulated by intrinsic and extrinsic factors, which may control the proliferation and/or maturation of neural progenitor cells. Adult-born neurons are integrated in preexisting networks and may have functional implications for adult brain. Here we attempt to summarize relevant findings concerning the physiological role of adult neurogenesis mainly focused on the subgranular zone, and to discuss the reduced neurogenesis observed during aging and the factors that have been involved in this phenomenon. Finally, we focus on hippocampal neurogenesis in Alzheimer's disease, reviewing animal models of the disease used for the study of this process and the conclusions that have been drawn in this context.