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Grant support

This work was supported by the Ministerio de Economia y Competitividad (SAF2013/42797-R and SAF2016/75959-R, JR), Ministerio de Educacion of Spain (PR2009-0169, JR), Comunidad de Madrid (S2010/BMD-2308, JR), Universidad Francisco de Vitoria (2017, JR), and the Research Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin (CJH), the National Institute on Drug Abuse (DA041212, CJH), and the National Multiple Sclerosis Society (RG 4432-A-5, BND).

Analysis of institutional authors

Lopez, AAuthor

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September 27, 2022
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Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer's disease

Publicated to:Journal Of Neuroinflammation. 15 (158): 158- - 2018-05-24 15(158), DOI: 10.1186/s12974-018-1174-9

Authors: Lopez, A; Aparicio, N; Pazos, MR; Grande, MT; Barreda-Manso, MA; Benito-Cuesta, I; Vazquez, C; Amores, M; Ruiz-Perez, G; Garcia-Garcia, E; Beatka, M; Tolon, RM; Dittel, BN; Hillard, CJ; Romero, J

Affiliations

BloodCtr Wisconsin, Blood Res Inst, Milwaukee, WI 53226 USA - Author
Hosp Univ Fdn Alcorcon, Lab Apoyo Invest, C Budapest 1, Madrid 28922, Spain - Author
Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA - Author
Med Coll Wisconsin, Neurosci Res Ctr, Milwaukee, WI 53226 USA - Author
Univ Francisco de Vitoria, Fac Expt Sci, Madrid 28223, Spain - Author
Univ Rey Juan Carlos, Mostoles, Spain - Author
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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 beta 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.

Keywords

Actin binding proteinActivationAif1 protein, mouseAlzheimer diseaseAmyloidAmyloid beta proteinAmyloid beta-peptidesAmyloid beta-protein (1-42)Amyloid plaqueAnalysis of varianceAnimalAnimal cellAnimal experimentAnimal modelAnimal tissueAnimalsArticleBrainBrain cortexBrain stemC57bl mouseCalcium binding proteinCalcium-binding proteinsCannabinoid 2 receptorCannabinoid cb 2 receptorCannabinoid cb2 receptorCd11b antigenCentral nervous systemControlled studyDeficiencyDisease modelDisease models, animalEnhanced green fluorescent proteinEnolaseFlow cytometryGene expression regulationGeneticsGliosisGreen fluorescent proteinGreen fluorescent proteinsHippocampusIn-vivoInflammationInterleukin 1betaLocalizationMacrophagesMaleMetabolismMiceMice, inbred c57blMice, transgenicMicrofilament proteinsMicrogliaMicroglial cellsModelMouseNervous system inflammationNeuroinflammationNonhumanPathologyPeptide fragmentPeptide fragmentsPhosphopyruvate hydratasePlaque, amyloidProtein expressionReceptor, cannabinoid, cb2Senile plaqueThalamusTransgenic miceTransgenic mouseUpregulation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Neuroinflammation due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2018, it was in position 40/267, thus managing to position itself as a Q1 (Primer Cuartil), in the category Neurosciences.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 2.72. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.32 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 16.82 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-02, the following number of citations:

  • WoS: 92
  • Scopus: 89

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 172.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 171 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 20.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 14 (Altmetric).
  • The number of mentions in news outlets: 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (López Sánchez, Antonio Francisco) .