Cannabinoid CB 2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer's Disease.

Autor:	Ruiz de Martín Esteban S; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Benito-Cuesta I; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Terradillos I; Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country UPV/EHU, Leioa, Spain., Martínez-Relimpio AM; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Arnanz MA; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Ruiz-Pérez G; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Korn C; Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland., Raposo C; Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland., Sarott RC; Laboratorium Für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland., Westphal MV; Laboratorium Für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland., Elezgarai I; Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country UPV/EHU, Leioa, Spain., Carreira EM; Laboratorium Für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland., Hillard CJ; Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, United States., Grether U; Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland., Grandes P; Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.; Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country UPV/EHU, Leioa, Spain., Grande MT; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain., Romero J; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2022 Apr 27; Vol. 13, pp. 841766. Date of Electronic Publication: 2022 Apr 27 (Print Publication: 2022).
DOI:	10.3389/fphar.2022.841766
Abstrakt:	The distribution and roles of the cannabinoid CB 2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB 2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB 2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer's disease. By using a novel mouse model (CB 2 EGFP/f/f ), we studied the distribution of cannabinoid CB 2 receptors in the 5xFAD mouse model of Alzheimer's disease (by generating 5xFAD/CB 2 EGFP/f/f mice) and explored the roles of CB 2 receptors in microglial function. We used a novel selective and brain penetrant CB 2 receptor agonist (RO6866945) as well as mice lacking the CB 2 receptor (5xFAD/CB 2 -/- ) for these studies. We found that CB 2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB 2 receptors as potential targets for the development of amyloid-modulating therapies. Competing Interests: Authors CK, CR and UG were employed by the company F. Hoffmann-La Roche Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Ruiz de Martín Esteban, Benito-Cuesta, Terradillos, Martínez-Relimpio, Arnanz, Ruiz-Pérez, Korn, Raposo, Sarott, Westphal, Elezgarai, Carreira, Hillard, Grether, Grandes, Grande and Romero.)
Databáze:	MEDLINE
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