Type 2 diabetes(T2D)is an independent risk factor for cognitive impairment.The dysregu-lation of hypoxia inducible factor(HIF)signaling in T2D patients results in impaired adaptive responses to hypoxia,thereby acceler...Type 2 diabetes(T2D)is an independent risk factor for cognitive impairment.The dysregu-lation 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 avail-able regarding its precise function in diabetes-associated cognitive impairment(DACI).Here,elevated HIF-1αlevels were observed in brain endothelial cells(ECs)of db/db mice.Functionally,brain ECs-specific knockdown of Hif1a 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 hip-pocampal lactate production through reduced LDHA expression.Notably,T2D patients showed increased cerebrospinal fluid lactate levels,which were strongly associated with their cognitive dysfunction.Intra-hippocampal injection of lactate accelerated cognitive dysfunction and impaired adult hippocampal neu-rogenesis(AHN)in db/db 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 db/db mice from cognitive impairment by decreasing brain endothelial HIF-1αexpression and subsequently reducing hippocampal lactate-induced AHN damage.Overall,this study elucidates the inhibiting role played by endothelial HIF-1α-driven lactate in AHN and highlights a poten-tial tactic of targeting HIF-1αin brain ECs for treating cognitive impairment.展开更多
基金supported by State Key Laboratory of Bioactive Molecules and Draggability Assessment,Jinan University(No.SKLBMDA-2024109,China)TCM Science and Technology Development Plan of Jiangsu Province(No.ZD202418,China)Qing Lan Project of Jiangsu Higher Education Institutions(China).
文摘Type 2 diabetes(T2D)is an independent risk factor for cognitive impairment.The dysregu-lation 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 avail-able regarding its precise function in diabetes-associated cognitive impairment(DACI).Here,elevated HIF-1αlevels were observed in brain endothelial cells(ECs)of db/db mice.Functionally,brain ECs-specific knockdown of Hif1a 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 hip-pocampal lactate production through reduced LDHA expression.Notably,T2D patients showed increased cerebrospinal fluid lactate levels,which were strongly associated with their cognitive dysfunction.Intra-hippocampal injection of lactate accelerated cognitive dysfunction and impaired adult hippocampal neu-rogenesis(AHN)in db/db 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 db/db mice from cognitive impairment by decreasing brain endothelial HIF-1αexpression and subsequently reducing hippocampal lactate-induced AHN damage.Overall,this study elucidates the inhibiting role played by endothelial HIF-1α-driven lactate in AHN and highlights a poten-tial tactic of targeting HIF-1αin brain ECs for treating cognitive impairment.
