Setmelanotide alleviates diabetes-associated cognitive impairment by interrupting the binding of ICAM-1 and JIP1 in endothelial cells of the blood-brain barrier.

Diabetes-associated cognitive impairment (DCI) is highly prevalent worldwide, but the mechanisms underlying this disorder remain unclear. Here we show that disruption of the blood-brain barrier (BBB) under hyperglycemic conditions is critical to the initiation and perpetuation of cognitive dysfunction. Proteomic analyses of brains from diabetic patients and non-diabetic patients revealed a substantial increase in the expression of intercellular adhesion molecule 1 (ICAM-1), which was confirmed with immunohistochemistry and immunoblotting. This upregulation was linked to cognitive deficits in patients, with a negative correlation between ICAM-1 levels and Montreal Cognitive Assessment scores. Increased ICAM-1 in microvascular endothelial cells (ECs) of the brain was necessary and sufficient to promote DCI in both diabetic patients and animal models. Using GST pull-down assays, surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and other methods, we found that the intracellular segment residues 522-526 of ICAM-1 bind directly to the phosphotyrosine interaction domain (PID) of JNK interacting protein 1 (JIP1; residues 586-593). This interaction damaged the integrity of endothelial tight junctions and was the key trigger for disrupting the BBB. After binding-site screening, setmelanotide was selected for study and was found to significantly reduce the interaction between ICAM-1 and JIP1, thereby allowing the integrity of EC tight junctions to be maintained. In diabetic mice, setmelanotide mitigated BBB damage and the resulting cognitive impairment. Together, our results reveal a novel mechanism for cognitive impairment after BBB injury, with the potential for new therapeutic applications in DCI.