Academic Journal
Setmelanotide alleviates diabetes-associated cognitive impairment by interrupting the binding of ICAM-1 and JIP1 in endothelial cells of the blood-brain barrier.
| Τίτλος: | Setmelanotide alleviates diabetes-associated cognitive impairment by interrupting the binding of ICAM-1 and JIP1 in endothelial cells of the blood-brain barrier. |
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| Συγγραφείς: | Wu SD; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Wang X; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China; National Demonstration Center for Experimental Basic Medical Science Education (Xuzhou Medical University)., Zhou YM; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Hu B; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Wang KY; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Yan CJ; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Zhu HY; The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Li H; Jiangsu Key Laboratory of Brain Disease and Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China., Wang XC; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China., Wang HP; Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China., Cheng AF; Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao, SAR, 999078, China., Zhu ZS; Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China. Electronic address: victorzhu2013@xzhmu.edu.cn., Ying CJ; Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China; Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.. Electronic address: ycj321651@163.com., Zhou XY; Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China. Electronic address: zhouxiaoyan0201@xzhmu.edu.cn. |
| Πηγή: | Metabolism: clinical and experimental [Metabolism] 2026 Oct; Vol. 183, pp. 156712. Date of Electronic Publication: 2026 Jul 24. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Inc Country of Publication: United States NLM ID: 0375267 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-8600 (Electronic) Linking ISSN: 00260495 NLM ISO Abbreviation: Metabolism Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York, NY : Elsevier Inc. Original Publication: New York, Grune & Stratton. |
| Ιατρικοί όροι (MeSH): | Blood-Brain Barrier*/drug effects , Blood-Brain Barrier*/metabolism , Intercellular Adhesion Molecule-1*/metabolism , Endothelial Cells*/metabolism , Endothelial Cells*/drug effects , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/etiology , Cognitive Dysfunction*/metabolism , Hypoglycemic Agents*/therapeutic use , Hypoglycemic Agents*/pharmacology, Protein Binding/drug effects ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/metabolism ; Animals ; Humans ; Mice ; Male ; Mice, Inbred C57BL |
| Περίληψη: | 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. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest All authors declare that they have no conflicts of interest. |
| Contributed Indexing: | Keywords: Binding sites; Blood–brain barrier; Diabetes-associated cognitive impairment; Intercellular adhesion molecule-1; JNK interacting protein 1; Setmelanotide |
| Substance Nomenclature: | 126547-89-5 (Intercellular Adhesion Molecule-1) 0 (Hypoglycemic Agents) |
| Entry Date(s): | Date Created: 20260724 Date Completed: 20260819 Latest Revision: 20260819 |
| Update Code: | 20260820 |
| DOI: | 10.1016/j.metabol.2026.156712 |
| PMID: | 42498078 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1532-8600 |
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| DOI: | 10.1016/j.metabol.2026.156712 |