Deciphering the CREB-NR2B axis: Unraveling the crosstalk of insulin and TGF-β signalling in ameliorating...

Postoperative cognitive dysfunction (POCD) is a significant postoperative complication, particularly in the elderly, linked to inflammation-mediated neural dysfunction. Insulin resistance and disruptions in transforming growth factor beta (TGF-β) signalling are associated with cognitive decline in aging, yet their roles in POCD are not fully understood. Here, we demonstrated that both insulin and TGF-β pathways were disrupted in POCD mouse models, with recombinant insulin and TGF-β treatments improving cognitive outcomes. These treatments reversed neuroinflammation in vitro, while CREB knockdown abrogated the protective effects, both in vivo and in vitro. Mechanistically, CREB was found to mediate the protective effects of insulin and TGF-β in POCD by directly regulating the expression of the cognitive-related protein NR2B. Altogether, our study identifies a key molecular target involved in the critical signalling pathways associated with POCD, offering promising therapeutic strategies for prevention and treatment.