Modifying Glucose Metabolism Reverses Memory Defects of Alzheimer's Disease Model at Late Stages

Abstract Significant efforts have harvested a sophisticated understanding of Alzheimer's disease (AD) including amyloid beta (Aβ) cascade mechanisms, although effective treatment for reversing or stopping AD progression is not available. This study reports that ferul enanthate (SL), a novel derivative of active agents targeting brain microvessels, oxidative phosphorylation, and ATP generation can reverse the hippocampus‐dependent spatial memory defects and reduce Aβ plaques in AD model mice (APP/PS1) at advanced stages. Spatial transcriptomics discovers that SL endows a cluster of genes expressing in Aging‐AD‐Rescue (AAR) pattern, which is prominent in hippocampal dendritic region where Aβ plaques are densely deposited. Furthermore, this AAR rule covers hippocampal Glut1 (glucose transporter 1) expression and ATP generation, which are further confirmed by immunoblotting or immunofluorescence studies. Our data demonstrate that SL can still reverse memory defects at advanced stages of AD mice by modifying aging‐dependent multiple pathologies of AD, particularly promoting Glut1 expression and ATP generation.