The Wnt signaling pathway is found somewhere in the midst of the exceedingly complicated network of processes that regulate regeneration and stem cell function. This small slice of cellular biochemistry has been an area of interest for researchers for quite some time. Firstly, Wnt signaling changes with age, as regenerative prowess diminishes. Secondly, adjusting Wnt signaling appears to be a practical basis for interventions aimed at tilting the balance of functions in aged tissue back towards greater stem cell activity, maintenance, and regeneration.

To pick a prominent example, the sizable biotech company Samumed is undertaking clinical development of Wnt signaling manipulation therapies to treat a broad range of age-related conditions. Further, as noted here, Wnt signaling is relevant to the maintenance and function of brain tissue via the creation of new neurons, a process known as neurogenesis. This is all very interesting, but it is worth noting that tinkering with Wnt signaling does not address underlying damage and causes of dysfunction: it is a way to force cells to act in more youthful ways despite damage and dysfunction. This can be beneficial where it succeeds, but is likely inferior to successful efforts to repair the underlying damage.

Role of Wnt Signaling in Adult Hippocampal Neurogenesis in Health and Disease

Studies indicate that the Wnt signaling plays multiple roles in adult hippocampal neurogenesis including neural progenitor cell (NPC) proliferation, fate-commitment, development and maturation of newborn neurons. Evidences suggest a stage-specific expression of particular receptors that might activate different Wnt signaling cascades to control the progression of neurogenesis. Although the role of the canonical Wnt co-receptor LRP6 support this notion, the role of other co-receptors that control the activation of non-canonical Wnt signaling remains to be elucidated. The identification of Wnt co-receptors involved in adult neurogenesis is a critical issue that should be addressed to gain a more comprehensive understanding of how canonical and non-canonical Wnt signaling are regulated during adult neurogenesis. In addition, it will be interesting to further study the downstream signaling components and effectors involved in the regulation of adult hippocampal neurogenesis by non-canonical Wnt signaling.

Several studies indicate that Wnt proteins released by hippocampal astrocytes and progenitor cells are crucial components of the subgranular zone (SGZ) neural stem cell niche. In addition, endogenous Wnt inhibitors are also components of the neurogenic microenvironment that dynamically regulate Wnt-mediated neurogenesis under physiological conditions. Considering the increasing number of Wnt regulators identified to date, it will be interesting to further investigate the contribution of these molecules to the dynamic control of neurogenesis.

In agreement with the critical roles of Wnt signaling in adult neurogenesis, evidence indicates that Wnt signaling is associated with the age-dependent decline in neurogenesis. Concomitantly with the decrease in the generation of new neurons, in normal aging there is a reduction in the expression of Wnt proteins, an increase in the expression of Wnt inhibitors, and a decrease in canonical Wnt signaling activity in the dentate gyrus. Wnt dysfunction might also underlie the impairment of neurogenesis observed in Alzheimer’s disease (AD).

Interestingly, genetic and pharmacological activation of Wnt signaling was shown to restore adult hippocampal neurogenesis, and also to improve cognitive performance in animal models of AD. Although it is not yet known how neurogenesis contribute to hippocampal function in humans, compelling evidence in animal models suggest that adult-born neurons are important for learning and memory, cognitive flexibility and mood regulation. In addition, recent findings support that neurogenesis impairment contributes to cognitive decline in aging and AD. Therefore, a better understanding on the molecular mechanisms involved in the regulation of neurogenesis may have important therapeutic implications.