Evaluation of the therapeutic potential of low dose chronic cannabidiol (CBD) treatment to reverse behavioural deficits of APPSwe/PS1?E9 transgenic female mice

Abstract

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease that causes behavioural and cognitive impairments and is hallmarked by amyloid plaques and neurofibrillary tangles of the protein tau. There is currently no cure for AD, with currently available treatments only targeting symptoms. Murine models of AD, such as the APPSwe/PS1I"E9 (APPxPS1) model, replicate important aspects of the disease and allow preclinical insights into the efficacy of other potential therapeutics. With evidence that targeting the endocannabinoid system may be therapeutic in AD, cannabidiol (CBD) has been of recent interest as to whether its anti-inflammatory, antioxidant and neuroprotective properties make it a potential therapeutic avenue for AD. In vitro and in vivo evidence shows that CBD indeed prevents and reverses AD-related amyloid plaques and neurofibrillary tangles, and cognitive decline including social and object recognition deficits. This thesis aimed to evaluate the therapeutic potential of chronic treatment with low dose CBD (5 mg/kg bodyweight) to reverse the behavioural deficits of APPxPS1 transgenic mice. Materials and Methods: 12-month-old control and transgenic female APPxPS1 mice were treated daily (post-onset of AD-like symptoms) via intraperitoneal injection with 5 mg/kg bodyweight CBD (or vehicle) starting three weeks prior to the assessment of a variety of behavioural paradigms. Mice were tested for anxiety, exploration and locomotion in the light dark test, motor functions including coordination and balance in the pole test and accelerod paradigms, object recognition memory, spatial learning and memory in the cheeseboard test, and sensorimotor gating using the acoustic prepulse inhibition paradigm. Results: APPxPS1 mice exhibited a hyper-locomotive phenotype in the light dark test, and CBD instigated more explorative-like behaviour in the dark zone in both genotypes. All mice showed similar motor function, and similar spatial learning rates, although APPxPS1 mice took longer to complete the cheeseboard training (due to a lower locomotion speed). All mice had intact spatial memory and retrieval memory, although APPxPS1 mice showed reduced levels of perseverance in the cheeseboard probe trial. Importantly, vehicle-treated APPxPS1 mice were characterised by object recognition deficits, which CBD recovered without impacting on control mice. Finally, all APPxPS1 mice exhibited a prepulse inhibition deficit regardless of treatment condition. Summary and Conclusion: APPxPS1 transgenic mice were hyper-locomotive and CBD elevated exploration in the dark zone of the light dark test. APPxPS1 females did not exhibit motor function deficits, and importantly CDB did not alter motor function in either APPxPS1 or control mice. Spatial learning and memory were not affected in APPxPS1 transgenic females. Importantly, 5 mg/kg CBD reversed novel object recognition deficits in APPxPS1 transgenic females suggesting a therapeutic-like effect in this established mouse model for AD. CBD did not reverse PPI deficits evident in transgenic females. Further research into the effects of CBD should consider investigating molecular mechanisms as well as testing other treatment designs including the consideration of other doses and ages of test animals. In conclusion, this study suggests that CBD has therapeutic value for particular behavioural impairments present in AD patients.

Date of Award	2019
Original language	English