title: Role of the cannabinoid system in the transit of beta-amyloid across the blood-brain barrier.
abstract: Emerging evidence suggests beta-amyloid (Aβ) deposition in the Alzheimer's disease (AD) brain is the result of impaired clearance, due in part to diminished Aβ transport across the blood-brain barrier (BBB). Recently, modulation of the cannabinoid system was shown to reduce Aβ 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 Aβ across the BBB. Using in vitro and in vivo models of BBB clearance, Aβ transit across the BBB was examined in the presence of cannabinoid receptor agonists and inhibitors. In addition, expression levels of the Aβ 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 Aβ clearance across the BBB (2-fold). Moreover, cannabinoid receptor inhibition negated the stimulatory influence of cannabinoid treatment on Aβ 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 Aβ 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 Aβ across the BBB. These findings provide insight into the mechanism by which cannabinoid treatment reduces Aβ burden in the AD brain and offer additional evidence on the utility of this pathway as a treatment for AD.
authors.affiliation: The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. Electronic address: cbachmeier@rfdn.org.
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
mesh_terms: D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid; Blood–brain barrier; Cannabinoid; Clearance; Low density lipoprotein receptor-related protein 1