Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice.

In the adult brain, canonical Wnt (Wnt/β-catenin) signaling modulates neuronal function, hippocampal neurogenesis, and synaptic plasticity. Indeed, growing evidence suggests that downregulation of Wnt signaling could be involved in the cognitive decline associated with aging and also with the physiopathology of Alzheimer's disease (AD). However, the molecular basis remains unknown. At present, SAMP8 is an experimental model that has been proposed for studying age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Here, we examined Wnt signaling in the hippocampus of SAMP8 mice at 9 and 12 months of age, as well as in its control-strain SAMR1 mice. Our results showed increased Dickkopf-1 protein levels in SAMP8 with age, in addition to GSK-3 α/β activation and hyperphosphorylated tau. Consequently, higher β-catenin phosphorylation at Ser(33,37) and Thr(41), which promotes its degradation, along with a decrease in active β-catenin (ABC) in the nucleus, were observed in SAMP8, mainly at the age of 12 months. Moreover, nuclear levels of Dvl3 were lower in 9- and 12-month-old SAMP8 mice. Related to these findings, SAMP8 showed an increase in neuronal loss in the hippocampus that was associated with lower protein levels of the antiapoptotic protein and the Wnt target gene, Bcl-2, in addition to an increase in the proapototic protein Bax. Our results suggest a relationship between age-related downregulation of canonical Wnt signaling and neuronal loss observed in the hippocampus of SAMP8 mice. Thus, enhancing Wnt signaling may represent a novel neuroprotective strategy aimed at counteracting the cognitive decline that is associated not only with aging but also with AD.