The effects of omega-3 fatty acids on Wnt activity in iPSC-derived neural stem cells from adult ADHD patients.

The canonical Wnt signaling pathway plays a key role in neurodevelopment and in maintaining cellular homeostasis of the central nervous system in adulthood. It regulates essential processes, such as cell proliferation, differentiation, and synaptogenesis. In vivo and genetic evidence suggests an association between attention-deficit/hyperactivity disorder (ADHD) and abnormalities in the Wnt pathway. Prior research from our group indicated heightened basal Wnt activity in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) of pediatric ADHD patients and showed that methylphenidate (MPH) and omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can modulate this pathway. While MPH is a first-line treatment for ADHD, ω-3 PUFAs are under investigation as a potential non-pharmacological supplement. Using the same functionality-based reporter technology, we assessed Wnt activity in iPSC-derived NSCs from 5 adult ADHD patients and 5 healthy controls. We examined whether ω-3 fatty acids (EPA and DHA), alone or combined, and DHA with MPH can modulate Wnt activity in these NSCs. Basal Wnt responsiveness did not differ between adult ADHD and control lines, although genetic risk for ADHD was associated with increased Wnt activity. EPA showed no statistically significant effects, while DHA strongly increased Wnt activity in both groups. DHA combined with EPA increased Wnt activity in ADHD lines, whereas DHA with MPH caused group-specific responses: enhancing Wnt signaling in ADHD but reducing it in controls. Compared to NSCs derived from children, adult-derived NSCs behave differently and show distinct responses to EPA and DHA, suggesting a potential route toward refined therapeutic strategies for adults.