Gastrodin alleviates Aβ25-35-induced glycolytic dysfunction via activating PI3K/AKT/BACH1 signaling in Alzheimer's disease models.

Cerebral glycolytic alteration has been identified as an important contributor to the pathological progress of Alzheimer's disease (AD). Research has shown that gastrodin (GAS) possesses neuroprotection in various experimental models of AD, but its specific mechanism remains unclear. In this study, we determined whether GAS exerted neuroprotective effects on AD models through regulating PI3K/AKT/BACH1 signaling axis. Eight-week-old C57BL/6 J male mice were intracerebroventricularly injected with Aβ25-35, to establish an AD model, followed by the administration of GAS (30, 60 mg·kg-1·d-1, i.g.) for 21 days. Treatment of GAS markedly alleviated the downregulation of p-PI3K Tyr199/458, p-AKT Ser473, BACH1 and HK1 in the hippocampus of the Aβ25-35-induced AD mice. To further explore the mechanism of GAS-mediated neuroprotection, an in vitro AD cellular model was established by challenging HT22 cells with Aβ25-35. In the Aβ25-35 induced cells, the expression of BACH1, p-PI3K Tyr199/458 and p-AKT Ser473 was reduced, the mRNA and protein levels of HK1 were decreased, and the levels of pyruvate and ATP were reduced. After treatment of GAS, the decline of these indicators was reversed. In addition, overexpression of BACH1 by lentivirus transfection significantly upregulated the mRNA and protein levels of HK1, thereby enhancing glycolytic function and protecting HT22 cells from Aβ25-35-induced injury. The results of chromatin immunoprecipitation assay-real-time quantitative PCR revealed that BACH1 directly bound to the HK1 promoter region. Collectively, these findings suggest that GAS can play a protective role in Aβ25-35-induced experimental AD models by increasing HK1 expression and ameliorating glycolytic dysfunction through activation of the PI3K/AKT/BACH1 signaling axis.