Role of the cannabinoid system in the transit of beta-amyloid across the blood-brain barrier

Emerging evidence suggests beta-amyloid (A beta) deposition in the Alzheimer's disease (AD) brain is the result of impaired clearance, due in part to diminished A beta transport across the blood-brain barrier (BBB). Recently, modulation of the cannabinoid system was shown to reduce A beta brain levels and improve cognitive behavior in AD animal models. The purpose of the current studies was to investigate the role of the cannabinoid system in the clearance of A beta across the BBB. Using in vitro and in vivo models of BBB clearance, A beta transit across the BBB was examined in the presence of cannabinoid receptor agonists and inhibitors. In addition, expression levels of the A beta transport protein, lipoprotein receptor-related protein1 (LRP1), were determined in the brain and plasma of mice following cannabinoid treatment. Cannabinoid receptor agonism or inhibition of endocannabinoid-degrading enzymes significantly enhanced A beta clearance across the BBB (2-fold). Moreover, cannabinoid receptor inhibition negated the stimulatory influence of cannabinoid treatment on A beta BBB clearance. Additionally, LRP1 levels in the brain and plasma were elevated following cannabinoid treatment (1.5-fold), providing rationale for the observed increase in A beta transit from the brain to the periphery. The current studies demonstrate, for the first time, a role for the cannabinoid system in the transit of A beta across the BBB. These findings provide insight into the mechanism by which cannabinoid treatment reduces A beta burden in the AD brain and offer additional evidence on the utility of this pathway as a treatment for AD. C) 2013 Elsevier Inc. All rights reserved.