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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Molecular neurobiology 2018-06, Vol.55 (6), p.4731-4744
Main Authors:	Wang, Lin, Liu, Bing-Jin, Cao, Yun, Xu, Wei-Qi, Sun, Dong-Sheng, Li, Meng-Zhu, Shi, Fang-Xiao, Li, Man, Tian, Qing, Wang, Jian-Zhi, Zhou, Xin-Wen
Format:	Article
Language:	eng
Subjects:	Adenylate Kinase - metabolism Aging - pathology Alzheimer Disease - complications Alzheimer Disease - pathology Alzheimer's disease Aminoimidazole Carboxamide - analogs & derivatives Aminoimidazole Carboxamide - pharmacology Animals Biomedical and Life Sciences Biomedicine Cannabinoid CB2 receptors Cannabinoids - pharmacology Cell Biology Clonal deletion Enzyme Activation Gene Deletion Glycogen Synthase Kinase 3 beta - metabolism Hippocampus - metabolism Hippocampus - pathology Memory Memory Disorders - complications Memory Disorders - pathology Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria Mitochondria - metabolism Neurobiology Neurology Neurosciences Pathology Phosphorylation Receptor, Cannabinoid, CB2 - agonists Receptor, Cannabinoid, CB2 - deficiency Receptor, Cannabinoid, CB2 - genetics Receptor, Cannabinoid, CB2 - metabolism Resveratrol Resveratrol - pharmacology Ribonucleotides - pharmacology RNA-mediated interference Signal Transduction SIRT1 protein Tau protein tau Proteins - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	0893-7648 1559-1182