POLYPHARMACOLOGICAL MODULATION OF AGE-RELATED COGNITIVE DECLINE IN SAMP8 MICE REVEALS SEX-SPECIFIC BEHAVIOURAL PROFILES

Sporadic Alzheimer’s disease (AD) is a multifactorial disorder for which effective disease-modifying treatments are still lacking. The Senescence Accelerated Mouse-Prone 8 (SAMP8) model is a non-transgenic model that spontaneously develops age-related cognitive decline together with mitochondrial dysfunction, oxidative stress, neuroinflammation, β-amyloid deposition and tau alterations. In this project, we performed a comprehensive characterization of SAMP8 pathophysiological features by profiling inflammatory and AD-related markers using ELISA, qPCR and flow cytometry. Moreover, we evaluated whether a polypharmacological approach targeting complementary pathogenic mechanisms could mitigate behavioural deficits in SAMP8 mice, while accounting for potential sex-dependent responses. Male and female SAMP8 mice were randomly assigned to receive either saline or a drug combination consisting of vardenafil (phosphodiesterase 5 inhibitor), roflumilast (phosphodiesterase 4 inhibitor) and liraglutide (glucagon-like peptide-1 receptor agonist) for two months. Behavioural assessments were conducted at baseline, one and two months after the combination therapy using the Open Field, Novel Object Recognition, Barnes Maze and Labyrinth tests. After one month, both sexes showed a trend toward increased locomotor activity, enhanced exploratory behaviour and reduced anxiety-like responses. After two months, males largely maintained these improvements across behavioural domains. In contrast, females displayed a more heterogeneous profile with impairments in selected Open Field parameters, but improved learning and spatial memory in the Barnes Maze. These results suggest that multi-target pharmacological interventions may beneficially modulate behavioural outcomes in SAMP8 mice, with marked sex-specific differences.