Sex-Dependent Effects of Chronic Cannabinoid Treatment on Repetitive Behaviors and Amyloid Burden in APP/PS1 Mice
Laura Vidal-Palencia, Jose Antonio González-Parra, Carla Ramon-Duaso, Arnau Busquets-GarciaIntroduction/Objective:
The endocannabinoid system has been linked to the pathophysiology of Alzheimer’s Disease (AD), which is accompanied by both neuropathological and behavioral alterations. However, the contribution of this system to these specific processes remains incompletely understood. Here, we investigated the effects of ACEA, a selective agonist of type-1 cannabinoid receptors (CB1R), on repetitive behaviors and amyloid load in the APP/PS1 mouse model of AD.
Methods:
ACEA for 21 days at 3 months of age, a presymptomatic stage, was administered in male and female APP/PS1 mice and evaluated using non-cognitive behavioral tasks, amyloid load, and CB1R expression.
results:
We revealed sex-dependent differences in repetitive behaviors. Molecular analyses further demonstrated that ACEA also modulates amyloid burden and CB1R expression in a brain region- and sex-specific manner. Additionally, we characterized distinct amyloid plaque types, offering new insights into the relationship between cannabinoid signaling and AD neuropathology.
Results:
By using two complementary behavioral paradigms, the splash test and the marble-burying test, we assessed the impact of cannabinoid treatment on male and female mice, revealing sex-dependent differences in repetitive behaviors. Molecular analyses further demonstrated that ACEA also modulates amyloid burden and CB1R expression, considering brain-region- and sex-specific parameters. Additionally, the study characterized distinct amyloid plaque types, offering new insights into the relationship between cannabinoid signaling and AD neuropathology.
Discussion:
The present findings demonstrate that cannabinoid-based interventions can influence both behavioral outcomes and molecular alterations associated with AD. Importantly, the observed effects appear to depend on biological sex and specific brain regions, emphasizing the need to consider these variables when designing cannabinoid-based therapeutic strategies for AD.
Conclusion:
Collectively, the study’s findings highlight a modulatory role of cannabinoid drugs in both behavioral and molecular aspects of AD, supporting their potential relevance as therapeutic targets tailored to sex and brain region.