Brain endothelial HIF-1α exacerbates diabetes-associated cognitive impairment by accelerating glycolysis-driven lactate production.
10.1016/j.apsb.2025.09.028
- Author:
Jicong CHEN
1
;
Ruohui LIN
1
;
Cuihua JIANG
2
;
Fang CHEN
3
;
Wei LI
4
;
Lei WANG
1
;
Ke PAN
1
;
Jian ZHANG
2
;
Zhiqi YIN
1
;
Yaping HUANG
1
Author Information
1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
3. Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China.
4. Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University (Nanjing Jiangning Hospital of Chinese Medicine), Nanjing 211100, China.
- Publication Type:Journal Article
- Keywords:
Adult hippocampal neurogenesis;
Asiatic acid;
Brain ECs;
Cognitive impairment;
Glycolysis;
HIF-1α;
Lactate;
Type 2 diabetes
- From:
Acta Pharmaceutica Sinica B
2025;15(11):5772-5788
- CountryChina
- Language:English
-
Abstract:
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-1α levels were observed in brain endothelial cells (ECs) of db/db mice. Functionally, brain ECs-specific knockdown of H if1 a 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 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-1α expression 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 potential tactic of targeting HIF-1α in brain ECs for treating cognitive impairment.
