Endocannabinoid regulation of amyloid-induced neuroinflammation

Neurobiol Aging. 2015 Nov;36(11):3008-3019. doi: 10.1016/j.neurobiolaging.2015.08.003. Epub 2015 Aug 15.


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.

Keywords: Amyloid; Endocannabinoid; Glia; Inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics*
  • Amidohydrolases / genetics
  • Amidohydrolases / metabolism
  • Amidohydrolases / physiology
  • Amyloid / metabolism
  • Animals
  • Disease Models, Animal
  • Endocannabinoids / metabolism*
  • Endocannabinoids / physiology
  • Female
  • Gliosis
  • Inflammation Mediators / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neurogenic Inflammation / etiology*
  • Neurogenic Inflammation / genetics*
  • Plaque, Amyloid
  • Receptors, Cannabinoid / metabolism*
  • Receptors, Cannabinoid / physiology
  • Spatial Memory


  • Amyloid
  • Endocannabinoids
  • Inflammation Mediators
  • Receptors, Cannabinoid
  • Amidohydrolases
  • fatty-acid amide hydrolase