Hamdan_2026_Front.Pharmacol_17_1793211

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurodegenerative malady marked by cognitive dysfunction and increased deposition of amyloid-beta and hyperphosphorylated tau proteins. Aluminum-associated neurotoxicity is well-documented and manifests itself in the form of cognitive dysfunction. Nutraceuticals, such as pomegranate extract (POM) or physical activity (PHA), have been recognized to exert beneficial actions on human wellbeing. This study aimed to mechanistically scrutinize the effects of POM and PHA either separately or in combination on AlCl(3)-induced AD in rats. METHODS: Sixty adult male Wistar rats were randomly assigned into five groups: control, AlCl(3), AlCl(3) + PHA, AlCl(3) + POM, and AlCl(3) + COMB (POM + PHA) and treated for 5 weeks. RESULTS: PHA and POM, either alone or in combination, exhibited a significant boost in memory and cognitive abilities, evidenced by the significant improvements in behavioral outcomes, elevations in monoamine (DA, NE, 5-HT), LRP1, and neprilysin levels, and reductions in acetylcholinesterase (ACHE) activity, APOE4 levels, and AD markers, relative to the AlCl(3)-intoxicated group. All treatments significantly ameliorated AlCl(3)-induced perturbations in antioxidant, neurotrophic, autophagic, inflammatory, endoplasmic reticulum (ER) stress, and apoptotic parameters, along with histopathological and immunohistochemical findings. These effects were demonstrated by the significant increase in antioxidant (Nrf2/HO-1/TAC/SOD), neurotrophic (PI3K/AKT/CREB/BDNF/TrKB), and autophagic (AMPK/SIRT-1/Beclin-1) markers, with significant reduction in neuroinflammatory (P38 MAPK/JNK/NF-kappaB/JAK-2/STAT-3/TNF-alpha/IL-1beta), ER stress (PERK/CHOP/GRP78), and apoptotic (BAX/P53/caspase-3) markers, relative to the AlCl(3)-intoxicated group. Interestingly, the combination exerted more favorable actions in all measured parameters and histological findings than the solo-treated groups. CONCLUSION: This study revealed the superiority of the combined therapy, compared to solo treatments, in alleviation of AlCl(3)-induced AD in rats, via adjustment of the Nrf2/HO-1, P38 MAPK/JNK/NF-kappaB/JAK-2/STAT-3, PI3K/AKT/GSK-3beta/CREB, AMPK/SIRT-1, PERK/CHOP, and apoptotic hubs.