Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer's Disease.

Jack Hashem,Chu Chen,Jian Zhang,Fei Gao,Mei Hu

doi:10.1007/s12035-021-02400-2

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates β-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3β and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.

Highlights

Alzheimer's disease (AD), the most common form of dementia, is a degenerative brain disease characterized by neuroinflammation, accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, neurodegeneration, synaptic dysfunction, and cognitive decline
Treatment with JZl184 significantly decreased hippocampal IL-1β and TNFα in both wild type (WT) and TG mice. These results indicate that inhibition of 2-AG metabolism with JZL184 reduces neuroinflammation in tau TG mice
monoacylglycerol lipase (MAGL) proposed as a therapeutic target is largely based on the studies using the APP transgenic models of AD [16,17,18,19, 27]

Summary

Introduction

Alzheimer's disease (AD), the most common form of dementia, is a degenerative brain disease characterized by neuroinflammation, accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, neurodegeneration, synaptic dysfunction, and cognitive decline. 2-AG is converted by cyclooxygenase-2 (COX-2) to a new class of prostaglandins, prostaglandin glycerol esters (PG-Gs), when COX-2 is excessively activated during inflammation [6, 7] These enzymes are capable of metabolizing of 2-AG, it has been estimated that 85% of 2-AG in the brain is degraded by MAGL [8, 9], suggesting that MAGL plays a dominant role in control of endogenous 2-AG levels in the brain. Previous studies from our group and others demonstrated that inactivation of MAGL reduces Aβ formation and accumulation, neuroinflammation and neurodegeneration and improves synaptic and cognitive functions in APP transgenic mice, animal models of AD [16,17,18,19] It is still not clear whether inhibition of 2AG metabolism mitigates tauopathies as intracellular neurofibrillary tangles that represent hyperphosphorylated tau proteins are an important neuropathological hallmark of AD [20, 21]. We show that inactivation of MAGL attenuates neuroinflammation and tau phosphorylation and prevents deterioration in synaptic proteins and cognitive decline in P301S/PS19 mice, a tau mouse model of AD, supporting generalizability of MAGL as a promising therapeutic target for AD

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Conclusion