1. OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3β/β-catenin pathway after subarachnoid hemorrhage.
- Author
-
Qiu JY, Gao SQ, Chen YS, Wang X, Zhuang YS, Miao SH, Zheng XB, Zhao R, Sun Y, and Zhou ML
- Subjects
- 3-Hydroxybutyric Acid, beta Catenin, Glycogen Synthase Kinase 3 beta, Proto-Oncogene Proteins c-akt, Animals, Mice, Coenzyme A-Transferases genetics, Coenzyme A-Transferases metabolism, Cognitive Dysfunction, Hippocampus growth & development, Neurogenesis, Subarachnoid Hemorrhage
- Abstract
Background: Subarachnoid hemorrhage (SAH) is a life-threatening neurological disease that usually has a poor prognosis. Neurogenesis is a potential therapeutic target for brain injury. Ketone metabolism also plays neuroprotective roles in many neurological disorders. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme of ketone body oxidation. In this study, we explored whether increasing ketone oxidation by upregulating OXCT1 in neurons could promote neurogenesis after SAH, and evaluated the potential mechanism involved in this process., Methods: The β-hydroxybutyrate content was measured using an enzymatic colorimetric assay. Adeno-associated virus targeting neurons was injected to overexpress OXCT1, and the expression and localization of proteins were evaluated by western blotting and immunofluorescence staining. Adult hippocampal neurogenesis was evaluated by dual staining with doublecortin and 5-Ethynyl-2'-Deoxyuridine. LY294002 was intracerebroventricularly administered to inhibit Akt activity. The Morris water maze and Y-maze tests were employed to assess cognitive function after SAH., Results: The results showed that OXCT1 expression and hippocampal neurogenesis significantly decreased in the early stage of SAH. Overexpression of OXCT1 successfully increased hippocampal neurogenesis via activation of Akt/GSK-3β/β-catenin signaling and improved cognitive function, both of which were reversed by administration of LY294002., Conclusions: OXCT1 regulated hippocampal ketone body metabolism and increased neurogenesis through mechanisms mediated by the Akt/GSK-3β/β-catenin pathway, improving cognitive impairment after SAH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF