Semaglutide to remodel mitochondrial dynamics and mitophagy balance for vascular dementia therapy

Abstract Vascular dementia (VaD) is a syndrome of cognitive dysfunction caused by cerebrovascular damage. At present, VaD is mainly prevented by controlling vascular risk factors clinically, while there has been limited progress in therapies directly targeting its pathological mechanism. Mitochondrial dysfunction plays a key role in the pathogenesis of VaD, but there are no drugs to improve VaD by regulating mitochondrial function in clinical practice. In this study, semaglutide was used as an intervention therapy and results showed that semaglutide could regulate the balance of mitochondrial dynamics and mitophagy by activating the phosphatidylinositol 3‐kinase/protein kinase B signaling pathway, adjust the phenotype of glial cells from the proinflammatory states to the anti‐inflammatory states, and improve cognitive dysfunction. This study identifies a therapeutic way of linking semaglutide to hippocampal neuronal protection, reduction of pathology, and restoration of cognitive function, with important implications for the treatment of VaD.