Mechanism and optimization of CBD-mediated analgesic effects (Admin Supplement)

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Project Summary The pathogenesis of Alzheimer’s Disease (AD) is a complex process involving multiple steps and players, which poses major challenges for mechanistic understanding and therapeutic development. The primary pathologic criteria for AD diagnosis include extracellular deposition of β-amyloid plaques and intracellular accumulation of tau neurofibrillary tangles. Clinical imaging studies suggest that the spatiotemporal spread of tau pathology typically starts from the entorhinal cortex and correlates closely with cognitive impairment. Furthermore, mechanistic research in animal models suggest that tau release and uptake across synaptically connected neurons are regulated by both neuronal and microglia activity. Due to the paucity of disease-modifying agents for AD, there is a critical need to test potential therapeutic strategies that may halt the spread of tau pathology by modulating neural and microglia activity. Cannabidiol (CBD) is the main non-psychoactive cannabinoid in Cannabis sativa with a range of reported pharmacological effects, including anti-inflammatory, anti-epileptic, and analgesic properties. The parent project of this research supplement is entitled “Mechanism and optimization of CBD-mediated analgesic effects”, with major goals to identify the neural mechanisms involved in the in vivo actions of CBD in order to optimize its analgesic effects. Our research from the parent project has provided evidence that CBD treatment modulates both neuronal and microglial activity in the brain with good safety profile. The overall objective of this AD-focused supplement is to investigate the mechanistic effects of CBD on the spread of tau pathology in mouse models. We hypothesize that CBD treatment can suppress excessive neural and microglial activity thereby reducing the spread of tau pathology in brain circuits. To explore this hypothesis, we will use a recently established, efficient viral vector model to study the propagation of human tau protein in mouse brain circuits. Specifically, we will determine if CBD suppresses activity-dependent propagation of tau protein from the entorhinal cortex, and if CBD alters microglia reactivity states to limit the spread of tau pathology. The outcomes of this research will inform potential development of cannabinoid-based therapies to reduce tau spreading in AD via suppression of excessive microglial and neuronal activity.