Sreenivasulu SuraSaravanan JagadeesanEmmanuel Oshiogwe OkwuofuKrishna Chaitanya Reddy DandalaSowmya RamakrishnappaSiti Saleha Binti MasrudinMohamad Aris Mohd Moklas0000-0002-8521-4854John Paul Judson0000-0001-6699-1618Quan Fu GanNurul Huda Mohd Nor2026-10-212026-10-212026-06-0410.1007/s11011-026-01894-whttps://dspace-cris.utar.edu.my/handle/123456789/11812Pathogenic tau hyperphosphorylation, together with reduced protein phosphatase 2 A (PP2A) expression, is associated with neurofibrillary tangle formation and cognitive deterioration in Alzheimer’s disease (AD). Cannabidiol (CBD), a non-psychotropic phytocannabinoid, remains insufficiently studied for its potential to modulate the PP2A–tau axis in experimental AD. This study evaluated whether CBD improves hippocampus-dependent spatial cognition in a D-galactose/AlCl? rat model of AD and whether these effects are associated with restoration of PP2A expression and attenuation of tau hyperphosphorylation. AD-like pathology was induced in male Wistar rats by D-galactose (60 mg/kg i.p.) and AlCl? (200 mg/kg oral gavage) for 10 weeks, followed by CBD (20, 40 or 80 mg/kg) or donepezil (1 mg/kg) for three weeks. The Morris water maze, Jess Simple Western, and ELISA were used to assess cognition, PP2A expression, and p-tau levels, respectively. CBD significantly improved spatial learning and memory. PP2A expression increased across all tested doses, with the highest mean level observed at 80 mg/kg. Hippocampal p-tau levels were significantly increased in the model group and significantly reduced by all CBD doses and donepezil (all p < 0.0001 vs. model). The inverse relationship between PP2A expression and p-tau levels suggests possible involvement of the PP2A–tau axis. CBD attenuated cognitive deficits and tau hyperphosphorylation alongside restoration of PP2A expression, suggesting that the PP2A–tau axis may be a relevant therapeutic target in AD-related tauopathy. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2026.en-USAlzheimer’s diseaseCannabidiolP-tauProtein phosphatase 2ASpatial memoryTau hyperphosphorylationAlzheimer DiseaseAnimalsCognition DisordersDisease ModelsAnimalHippocampusMaleMaze LearningPhosphorylationProtein Phosphatase 2RatsWistartau Proteinscannabidiolphosphoprotein phosphatase 2tau proteinAlzheimer diseaseanimalbiosynthesiscognitive defectdisease modeldrug effectdrug therapyhippocampusmalemaze testmetabolismphosphorylationratWistar ratjournal-article