During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Despite Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and postsynaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype in not yet established but when the cognitive decline starts.

Alzheimer’s disease (AD) is the most common type of dementia. The onset and progression of this pathology are correlated with several changes in the brain, including the formation of extracellular aggregates of amyloid-beta (Aβ) peptide and the intracellular accumulation of hyperphosphorylated tau protein. In addition, dysregulated neuronal plasticity, synapse loss, and a reduction in cellular energy metabolism have also been described. Canonical Wnt signaling has also been shown to be downregulated in AD. Remarkably, we showed previously that the in vivo inhibition of Wnt signaling accelerates the appearance of AD markers in transgenic (Tg) and wild-type (WT) mice. Additionally, we found that Wnt signaling stimulates energy metabolism, which is critical for the ability of Wnt to promote the recovery of cognitive function in AD. Therefore, we hypothesized that activation of canonical Wnt signaling in a presymptomatic transgenic animal model of AD would improve some symptoms. To explore the latter, we used a transgenic mouse model (J20 Tg) with mild AD phenotype expression (high levels of amyloid aggregates) and studied the effect of andrographolide (ANDRO), an activator of canonical Wnt signaling. We found that presymptomatic administration of ANDRO in J20 Tg mice prevented the reduction in cellular energy metabolism markers. Moreover, treated animals showed improvement in cognitive performance. At the synaptic level, J20 Tg animals showed severe deficiencies in presynaptic function as determined by electrophysiological parameters, all of which were completely restored to normal by ANDRO administration. Finally, an analysis of hippocampal synaptosomes by electron microscopy revealed that the length of synapses was restored with ANDRO treatment. Altogether, these data support the idea that the activation of canonical Wnt signaling during presymptomatic stages could represent an interesting pharmacological strategy to delay the onset of AD.