Endocannabinoid regulation of amyloid-induced neuroinflammation

NEUROBIOLOGY OF AGING

卷:36

Article

Vazquez, Carmen¹  Tolon, Rosa M.¹  Teresa Grande, M.²  Caraza, Marina^1,2  Moreno, Marta¹  Koester, Erin C.^3,4  Villaescusa, Borja¹  Ruiz-Valdepenas, Lourdes¹  Javier Fernandez-Sanchez, Francisco¹  Cravatt, Benjamin F.^5,6,7  Hillard, Cecilia J.^3,4  Romero, Julian^1,2 

[1] Hosp Univ Fdn, Lab Apoyo Invest, Madrid 28922, Spain

[2] Univ Francisco Vitoria, Sch Biosci, Madrid, Spain

[3] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA

[4] Med Coll Wisconsin, Neurosci Res Ctr, Milwaukee, WI 53226 USA

[5] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[6] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA

[7] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

关键词: Endocannabinoid;    Amyloid;    Inflammation;    Glia;   

DOI  :  10.1016/j.neurobiolaging.2015.08.003

来源: Elsevier

【 摘 要 】

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 inflammed brain. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

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