Brain endothelial HIF-1α exacerbates diabetes-associated cognitive impairment by accelerating glycolysis-driven lactate production

Type 2 diabetes (T2D) is an independent risk factor for cognitive impairment. The dysregulation of hypoxia inducible factor (HIF) signaling in T2D patients results in impaired adaptive responses to hypoxia, thereby accelerating the progression of complications. However, limited knowledge is available regarding its precise function in diabetes-associated cognitive impairment (DACI). Here, elevated HIF-1<i>α</i> levels were observed in brain endothelial cells (ECs) of <i>db</i>/<i>db</i> mice. Functionally, brain ECs-specific knockdown of <i>H</i> <i>if1</i> <i>a</i> significantly ameliorated T2D-induced memory loss and neuronal damage. Glycolysis in brain ECs was inhibited in this process, as indicated by RNA-seq, leading to decreased hippocampal lactate production through reduced LDHA expression. Notably, T2D patients showed increased cerebrospinal fluid lactate levels, which were strongly associated with their cognitive dysfunction. Intrahippocampal injection of lactate accelerated cognitive dysfunction and impaired adult hippocampal neurogenesis (AHN) in <i>db</i>/<i>db</i> mice. Conversely, reducing hippocampal lactate levels through the intrahippocampal injection of oxamate delayed the onset of memory deficits. Furthermore, asiatic acid was discovered to protect <i>db</i>/<i>db</i> mice from cognitive impairment by decreasing brain endothelial HIF-1<i>α</i> expression and subsequently reducing hippocampal lactate-induced AHN damage. Overall, this study elucidates the inhibiting role played by endothelial HIF-1<i>α</i>-driven lactate in AHN and highlights a potential tactic of targeting HIF-1<i>α</i> in brain ECs for treating cognitive impairment.