Chronic Treatment with 50 mg/kg Cannabidiol Improves Cognition and Moderately Reduces A beta(40) Levels in 12-Month-Old Male A beta PPswe/PS1 Delta E9 Transgenic Mice

Alzheimer's disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-beta (A beta) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the A beta PPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dosedependent manner. Thus, this study determined the chronic effects of 50 mg/kg CBD in male A beta PPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male A beta PPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble A beta 40 levels in the hippocampus of A beta PPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPAR beta markers in the cortex. This study demonstrates that therapeuticlike effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in A beta PPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble A beta 40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation.