Endocannabinoid regulation of amyloid-induced neuroinflammation. Neurobiol Aging 2015 Nov;36(11):3008-3019
Date
09/13/2015Pubmed ID
26362942DOI
10.1016/j.neurobiolaging.2015.08.003Scopus ID
2-s2.0-84947041175 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
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.
Author List
Vázquez C, Tolón RM, Grande MT, Caraza M, Moreno M, Koester EC, Villaescusa B, Ruiz-Valdepeñas L, Fernández-Sánchez FJ, Cravatt BF, Hillard CJ, Romero JAuthor
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Alzheimer DiseaseAmidohydrolases
Amyloid
Animals
Disease Models, Animal
Endocannabinoids
Female
Gliosis
Inflammation Mediators
Male
Mice, Inbred C57BL
Mice, Transgenic
Molecular Targeted Therapy
Neurogenic Inflammation
Plaque, Amyloid
Receptors, Cannabinoid
Spatial Memory