id_765. CANNABINOID RESCUE OF MEMORY DEFICITS THROUGH ASTROGLIAL LIPID METABOLISM IN ALZHEIMER’S DISEASE
Carla Ramon-Duaso1, Júlia S. Pinho2, Xoel Mato-Blanco3, Pau Berenguer-Molins3, Júlia Perera-Bel3, Arnau Busquets-Garcia1
1 Hospital del Mar Research Institute, Cell-type mechanisms in normal and pathological behavior, Barcelona, Spain.
2 Gulbenkian Institute for Molecular Medicine, Oeiras, Portugal
3 Hospital del Mar Research Institute, MARData-BU, Barcelona, Spain.
INTRODUCTION: Astrocytes contribute to Alzheimer’s disease (AD) through metabolic and functional alterations, yet the link between astroglial dysfunction, memory deficits, and cannabinoid signaling remains unclear.
AIM(S): To investigate sex-, genotype-, and cannabinoid-dependent effects on memory and astrocyte biology in the APP/PS1 mouse model, focusing on astroglial lipid metabolism.
METHOD(S): Male and female wild-type and APP/PS1 mice received chronic cannabinoid treatment during the presymptomatic stage and were assessed longitudinally using the Novel Object Recognition Task and contextual fear conditioning. Astrocytic activity in dorsal CA1 was selectively modulated during memory consolidation. In vivo fiber photometry monitored hippocampal astrocytic calcium dynamics during behavior. Single-cell RNA sequencing characterized astrocyte-specific transcriptional changes related to lipid metabolism.
RESULTS: Male APP/PS1 mice showed recognition memory deficits that were prevented by cannabinoid treatment, while female mice exhibited fear memory impairments that were not rescued. Modulation of dorsal CA1 astrocytes restored recognition memory. Fiber photometry revealed sex-, genotype-, and cannabinoid-dependent alterations in astrocytic calcium signaling. Single-cell RNA sequencing identified disrupted astroglial lipid metabolism in male APP/PS1 mice that was normalized by cannabinoid treatment.
CONCLUSIONS: Cannabinoid treatment preserves memory in association with restored astroglial lipid metabolism and calcium signaling, highlighting astrocytes as key mediators of cognitive deficits and therapeutic targets in AD.
FINANCIAL SUPPORT: Project RTI2018-093667-A-100