Delta-9-tetrahydrocannabinol (Δ⁹-THC) modulates cognition, hippocampal cellular integrity and alzheimer-related protein markers in a D-galactose + A1C1₃-induced wistar rat model

Alzheimer’s disease (AD) is a complex, progressive neurodegenerative disorder characterized by a gradual decline in cognitive functions, especially memory and learning, due to synaptic dysfunction and neuronal loss in the hippocampus and associated cortical regions. Central pathological features include extracellular deposition of amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau. Despite extensive research, current pharmacological interventions are largely palliative, underscoring the need for novel therapeutic strategies capable of modifying disease progression. Delta-9-tetrahydrocannabinol (Δ9THC), the primary psychoactive constituent of Cannabis sativa, has garnered increasing interest for its neuroprotective, anti-inflammatory, and neuromodulatory properties. Importantly, recent findings suggest that Δ9THC may also support adult hippocampal neurogenesis, a process closely linked to learning, memory, and cognitive resilience. This study aims to elucidate the neurotherapeutic potential of Δ9THC in AD-induced Wistar rats animal model via administrating 200mg/kg of AlCl3 and 60 mg/kg of D-galactose to induce Alzheimer-like degenerative properties in a total of 10 weeks. Upon treatment, behavioural results demonstrated by the Δ9THC-treated AD rats exhibited significantly improved spatial learning and memory retention compared to untreated AD counterparts. At the cellular level, Δ9THC treatment was associated with a substantial reduction of apoptotic neuronal cells. Crucially, Δ9THC also promoted the expression of neurogenesis markers and improved synaptic protein levels, suggesting an enhancement in both neuronal regeneration and synaptic plasticity. Along with that, Δ9THC has further proved its ability through the significant downregulation of protein levels BACE1 and p-tau Thr231 in AD-induced brains as portrayed in the western blot protein bands. In conclusion, this study provides compelling evidence that Δ9THC exerts multifaceted neurotherapeutic effects in an Alzheimer’s disease model, improving cognitive outcomes by mitigating neuronal death through preserving neuronal integrity, and potentially enhancing adult neurogenesis and reducing key pathological hallmarks, BACE1 and p-tau Thr231 that lead to formation of plaques and tangles throughout the disease progression. From this study, the outcome emphasised the therapeutic promise of Δ9THC in targeting not only pathological hallmarks of AD but also in promoting mechanisms essential for cognitive recovery and neural enhancement for learning and memory.