Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer's Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3β Pathway

Mol Neurobiol. 2018 Jun;55(6):4731-4744. doi: 10.1007/s12035-017-0676-2. Epub 2017 Jul 17.


Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer's disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R-/- mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R-/- mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R-/- mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3β activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3β disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3β pathway. These findings proved that CB2R/AMPK/GSK3β pathway can be a promising new drug target for AD.

Keywords: AMPK; Alzheimer’s disease; Tau; Type 2-cannabinoid receptors.

MeSH terms

  • Adenylate Kinase / metabolism*
  • Aging / pathology
  • Alzheimer Disease / complications
  • Alzheimer Disease / pathology*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Cannabinoids / pharmacology
  • Enzyme Activation
  • Gene Deletion*
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Memory
  • Memory Disorders / complications
  • Memory Disorders / pathology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Phosphorylation
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / deficiency
  • Receptor, Cannabinoid, CB2 / genetics*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Resveratrol / pharmacology
  • Ribonucleotides / pharmacology
  • Signal Transduction
  • tau Proteins / metabolism*


  • Cannabinoids
  • Receptor, Cannabinoid, CB2
  • Ribonucleotides
  • tau Proteins
  • Aminoimidazole Carboxamide
  • Glycogen Synthase Kinase 3 beta
  • Adenylate Kinase
  • AICA ribonucleotide
  • Resveratrol
  • 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC