Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL) is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ) associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning, and memory in AD animals. Although the molecular mechanisms underlying the beneficial effects produced by MAGL inhibition remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD, and thus is a promising therapeutic target for the prevention and treatment of AD.

• Authors: Rongqing Chen, Jian Zhang, Yan Wu, Dongqing Wang, Guoping Feng, Ya-Ping Tang, Zhaoqian Teng, Chu Chen
• Journal: Cell reports (Cell Rep) Vol. 2 Issue 5 Pg. 1329-39 (Nov 29 2012) ISSN: 2211-1247 [Electronic] United States
• PMID: 23122958 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Benzodioxoles
• JZL 184
• Piperidines
• Receptor, Cannabinoid, CB1
• Receptor, Cannabinoid, CB2
• Monoacylglycerol Lipases
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (enzymology, pathology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Aspartic Acid Endopeptidases (metabolism)
• Astrocytes (metabolism)
• Benzodioxoles (pharmacology)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Hippocampus (chemistry, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Microglia (metabolism)
• Monoacylglycerol Lipases (antagonists & inhibitors, metabolism)
• Neuronal Plasticity
• Piperidines (pharmacology)
• Receptor, Cannabinoid, CB1 (metabolism)
• Receptor, Cannabinoid, CB2 (metabolism)
• Synapses (physiology)