Faculty Collaboration Database

Cannabinoid CB₂ receptors in the mouse brain: relevance for Alzheimer's disease. J Neuroinflammation 2018 May 24;15(1):158

Date

05/26/2018

Pubmed ID

29793509

Pubmed Central ID

PMC5968596

DOI

10.1186/s12974-018-1174-9

Scopus ID

2-s2.0-85047540052 (requires institutional sign-in at Scopus site)   92 Citations

Abstract

BACKGROUND: Because of their low levels of expression and the inadequacy of current research tools, CB₂ cannabinoid receptors (CB₂R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s).

METHODS: We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the control of the cnr2 gene promoter through the insertion of an Internal Ribosomal Entry Site followed by the EGFP coding region immediately 3' of the cnr2 gene and crossed these mice with mice expressing five familial Alzheimer's disease (AD) mutations (5xFAD).

RESULTS: Expression of EGFP in control mice was below the level of detection in all regions of the central nervous system (CNS) that we examined. CB₂R-dependent-EGFP expression was detected in the CNS of 3-month-old AD mice in areas of intense inflammation and amyloid deposition; expression was coincident with the appearance of plaques in the cortex, hippocampus, brain stem, and thalamus. The expression of EGFP increased as a function of plaque formation and subsequent microgliosis and was restricted to microglial cells located in close proximity to neuritic plaques. AD mice with CB₂R deletion exhibited decreased neuritic plaques with no changes in IL1β expression.

CONCLUSIONS: Using a novel reporter mouse line, we found no evidence for CB₂R expression in the healthy CNS but clear up-regulation in the context of amyloid-triggered neuroinflammation. Data from CB₂R null mice indicate that they play a complex role in the response to plaque formation.

Author List

López A, Aparicio N, Pazos MR, Grande MT, Barreda-Manso MA, Benito-Cuesta I, Vázquez C, Amores M, Ruiz-Pérez G, García-García E, Beatka M, Tolón RM, Dittel BN, Hillard CJ, Romero J

Author

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Amyloid beta-Peptides
Analysis of Variance
Animals
Brain
CD11b Antigen
Calcium-Binding Proteins
Disease Models, Animal
Flow Cytometry
Gene Expression Regulation
Green Fluorescent Proteins
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microfilament Proteins
Peptide Fragments
Phosphopyruvate Hydratase
Plaque, Amyloid
Receptor, Cannabinoid, CB2