title: Endocannabinoid regulation of amyloid-induced neuroinflammation.
abstract: The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflamed brain.
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vázquez
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Tolón
authors.affiliation: School of Biosciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Grande
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain; School of Biosciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Caraza
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Koester
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Villaescusa
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ruiz-Valdepeñas
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Fernández-Sánchez
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA; Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, USA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.affiliation: Department of Pharmacology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.affiliation: Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain; School of Biosciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain. Electronic address: jromerop@fhalcorcon.es.
authors.forename: Julián
authors.initials: J
authors.lastname: Romero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005911:Gliosis; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D020078:Neurogenic Inflammation / Q000209:etiology* / Q000235:genetics*; D058225:Plaque, Amyloid; D043882:Receptors, Cannabinoid / Q000378:metabolism* / Q000502:physiology; D065852:Spatial Memory; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000682:Amyloid; D063388:Endocannabinoids; D018836:Inflammation Mediators; D043882:Receptors, Cannabinoid; D000099252:Fatty Acid Amide Hydrolases
keywords: Amyloid; Endocannabinoid; Glia; Inflammation