ASTROGLIAL LIPID METABOLISM LINKS CANNABINOID SIGNALING TO MEMORY DEFICITS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Astrocytes play a central role in Alzheimer’s disease (AD), contributing not only to neuroinflammation and metabolic alterations but also to cognitive dysfunction;however, the mechanisms linking astroglial activity to behavioral deficits and AD progression remain incompletely understood.This study aimed to investigate sex-, genotype-, and cannabinoid-dependent effects across behavioral, functional, and molecular levels using the APP/PS1 mouse model of AD.Longitudinal behavioral analyses revealed marked sex- and genotype-dependent cognitive alterations that were differentially modulated by chronic treatment with a cannabinoid compound administered during the presymptomatic stage. Male APP/PS1 mice exhibited pronounced impairments in the Novel Object Recognition Task (NORT), which were prevented by cannabinoid treatment, whereas female mice showed deficits in contextual fear memory that were not rescued by this pharmacological intervention.To assess the contribution of astrocytes to recognition memory, astrocytic activity was selectively modulated in the dorsal CA1 hippocampus during the memory consolidation phase in male wild-type and APP/PS1 mice, resulting in a restoration of recognition memory performance and indicating a critical role for astrocytic dynamics in cognitive processing. In parallel, in vivo fiber photometry was used to monitor hippocampal astrocytic calcium signaling during NORT performance, revealing sex-, genotype-, and cannabinoid-dependent alterations in astrocytic activity patterns.At the molecular level, single-cell RNA sequencing of hippocampal tissue identified disruptions in astrocytic lipid metabolism-related gene expression in male APP/PS1 mice, which were modulated by cannabinoid treatment. Together, these findings identify astrocytic calcium signaling and lipid-related pathways as key correlates of sex-specific cognitive deficits in AD and highlight astrocytes as promising targets for therapeutic intervention.