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Endocannabinoid regulation of amyloid-induced neuroinflammation. Neurobiol Aging 2015 Nov;36(11):3008-3019

Date

09/13/2015

Pubmed ID

26362942

DOI

10.1016/j.neurobiolaging.2015.08.003

Scopus ID

2-s2.0-84947041175 (requires institutional sign-in at Scopus site)   28 Citations

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.

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 J

Author

Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Alzheimer Disease
Amidohydrolases
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