Dataset Information

Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer's disease.

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 IL1? 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.

SUBMITTER: Lopez A

PROVIDER: S-EPMC5968596 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Cannabinoid CB<sub>2</sub> receptors in the mouse brain: relevance for Alzheimer's disease.

López Alicia A Aparicio Noelia N Pazos M Ruth MR Grande M Teresa MT Barreda-Manso M Asunción MA Benito-Cuesta Irene I Vázquez Carmen C Amores Mario M Ruiz-Pérez Gonzalo G García-García Elena E Beatka Margaret M Tolón Rosa M RM Dittel Bonnie N BN Hillard Cecilia J CJ Romero Julián J

Journal of neuroinflammation 20180524 1

<h4>Background</h4>Because of their low levels of expression and the inadequacy of current research tools, CB<sub>2</sub> cannabinoid receptors (CB<sub>2</sub>R) 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).<h4>Methods</h4>We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the ...[more]

PMID: 29793509

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Project description:DAT-Cnr2 mice are conditional knockout (cKO) animals that do not express cannabinoid CB2 receptors (CB2R), in midbrain dopamine neurons. The hyperactivity phenotype of DAT-Cnr2 cKO mice were paradoxically reduced by low dose of amphetamine. Here, we report on the locomotor activity analysis in male and female adolescent (PND 30 ± 2) mice in basal conditions and in response to different doses of amphetamine, using the Open Field (OF), Elevated Plus-Maze (EPM) tests and the Novel Object Recognition (NOR) task as a putative model of attention deficit hyperactivity disorder (ADHD). Results showed that both male and female adolescent DAT-Cnr2 mice displayed significant increases in distance traveled in the OF test compared with WT mice. However, 2 mg/kg dose of amphetamine reduced the distance traveled by the DAT-Cnr2 but was increased in the WT mice. In the EPM test of anxiety-like behavioral responses, DAT-Cnr2 spent more time in the open arms of the maze than the WT mice, suggesting a reduction in anxiety-like response. DAT-Cnr2 mice showed significant increase in the number of unprotected head dips in the maze test and in the cliff avoidance reaction (CAR) test demonstrating impulsivity and risky behavior. DAT-Cnr2 mice also exhibited deficient response in the delay decision making (DDM), with impulsive choice. Both DAT-Cnr2 and WT were able to recognize the new object in the NOR task, but the exploration by the DAT-Cnr2 was less than that of the WT mice. Following the administration of 2 mg/kg of amphetamine, the similarities and differential performances of the DAT-Cnr2 and WT mice in the EPM test and NOR task was probably due to increase in attention. Microglia activation detected by Cd11b immunolabelling was enhanced in the hippocampus in DAT-Cnr2 cKO than in WT mice, implicating neuro-immune modulatory effects of CB2R. The results demonstrates that DAT-Cnr2 cKO mice with cell-type specific deletion of CB2R in midbrain dopaminergic neurons may represent a possible model for studying the neurobiological basis of ADHD.

Project description:In Alzheimer's disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.

Dataset Information

Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer's disease.

Publications

Cannabinoid CB<sub>2</sub> receptors in the mouse brain: relevance for Alzheimer's disease.

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