Summary
As we get older, our brains produce fewer new neurons, which affects our ability to think and remember things. Scientists have discovered a pathway involving a protein called WIP1 that plays a role in this decline. They found that boosting levels of WIP1 in older mice increased the number of neural stem cells and improved the formation of new neurons. This also helped the mice perform better on tasks involving their sense of smell.
Further research showed that WIP1 works by controlling another protein called DKK3, which normally blocks the formation of new neurons. By blocking DKK3 or activating a pathway called WNT signaling, scientists were able to increase neuron formation and improve the mice’s sense of smell.
These findings suggest that manipulating WIP1 levels could potentially help prevent some of the declines in brain function associated with aging.
Scientific Abstract
The number of newly formed neurons declines rapidly during aging, and this decrease in neurogenesis is associated with decreased function of neural stem/progenitor cells (NPCs). Here, we determined that a WIP1-dependent pathway regulates NPC differentiation and contributes to the age-associated decline of neurogenesis. Specifically, we found that WIP1 is expressed in NPCs of the mouse subventricular zone (SVZ) and aged animals with genetically enhanced WIP1 expression exhibited higher NPC numbers and neuronal differentiation compared with aged WT animals. Additionally, augmenting WIP1 expression in aged animals markedly improved neuron formation and rescued a functional defect in fine odor discrimination in aged mice. We identified the WNT signaling pathway inhibitor DKK3 as a key downstream target of WIP1 and found that expression of DKK3 in the SVZ is restricted to NPCs. Using murine reporter strains, we determined that DKK3 inhibits neuroblast formation by suppressing WNT signaling and Dkk3 deletion or pharmacological activation of the WNT pathway improved neuron formation and olfactory function in aged mice. We propose that WIP1 controls DKK3-dependent inhibition of neuronal differentiation during aging and suggest that regulating WIP1 levels could prevent certain aspects of functional decline of the aging brain.