Restoring glucose metabolism in Alzheimer's disease by targeting integrated stress response

Cerebral glucose hypometabolism has been consistently associated with Alzheimer's disease (AD). With extensive efforts to eliminate AD pathologies, including the removal of amyloid-β ​(Aβ) plaques and hyperphosphorylated Tau, strategies aimed at restoring glucose metabolism in the brain regions most affected by AD are believed to have significant clinical implications. In this study, we demonstrated that glucose hypometabolism preceded neuronal death in triple-transgenic AD (3xTg-AD) mice, likely attributable to reduced expression of glucose transporter type 1 (GLUT1) or glucose transporter type 3 (GLUT3). Furthermore, we observed aberrant activation of the integrated stress response (ISR) pathway in AD models, with Aβ and Tau phosphorylation contributing to the activation of the ISR and subsequent reduction in GLUT1/3 expression. Inhibiting ISR activation by utilizing the ISR inhibitor ISRIB can effectively restore GLUT1/3 expression in both in vitro and in vivo models. Importantly, ISRIB treatment improved cognitive function and brain glucose metabolism in 3xTg-AD mice. Our findings suggest that targeting the ISR pathway to restore GLUTs expression may be a potential therapeutic strategy for AD.