The therapeutic potential of the phytocannabinoid cannabidiol (CBD) for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterised by progressive cognitive decline and by the accumulation of amyloid-I² (AI²) and tau hyperphosphorylation in the brain 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 making it an interesting therapeutic candidate for AD therapy. Previous studies in male APPswe/PS1I"E9 (APPxPS1) transgenic mice revealed that the beneficial cognitive effects of CBD are only associated with subtle changes in neuropathological measures. Importantly, CBD has been shown to work in a dose-dependent manner and cannabinoids are known to have biphasic effects. The aims of my thesis were to investigate the therapeutic potential of 50 and 100 mg/kg CBD in male APPxPS1 transgenic mice, to conduct a comprehensive behavioural analysis of a novel tauopathy mouse model of AD, TAU58/2 transgenic mice, and to investigate the therapeutic potential of 50 mg/kg CBD in the latter mouse model. Chronic CBD treatment (50 and 100 mg/kg) reversed cognitive deficits in APPxPS1 transgenic mice. In addition, chronic CBD treatment at a dose of 50 mg/kg tended to reduce insoluble Ab40 pathology in the hippocampus. However, chronic CBD treatment did not affect markers of neuroinflammation and neurodegeneration at the ages and doses tested. 4-month-old TAU58/2 males demonstrated a number of AD-relevant behavioural impairments, highlighting its relevance as a tauopathy mouse model of AD. However, chronic CBD treatment did not reverse motor impairments in 4-month-old TAU58/2 males. The findings in this thesis indicate that CBD demonstrates therapeutic benefits on cognition, emphasizing the clinical relevance of CBD treatment in AD. However, the underlying mechanisms involved and the effectiveness of CBD on tauopathy mouse models requires further investigation.

Date of Award	2020
Original language	English