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

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.

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Data Availability

Data supporting the findings of this manuscript are available from the corresponding authors upon request.

Code Availability

Not applicable.

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Acknowledgements

The authors also thank NIH Mental Health Institute Chemical Synthesis and Drug Supply Program for providing JZL184.

Funding

This work was supported by National Institutes of Health grants R01NS076815, R01MH113535, and R01AG058621 (to C.C.) and by startup funds from UT Health San Antonio, Joe R. & Teresa Lozano Long School of Medicine (to C.C.).

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C.C. conceived the project and designed the experiments; J.H., M.H., J.Z., F.G., and C.C. performed the experiments and analyzed the data; C.C. supervised the work and wrote the manuscript.

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Correspondence to Chu Chen.

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All the animal experiments were performed in compliance with the US Department of Health and Human Services Guide for the Care and Use of Laboratory Animals. The care and use of the animals reported in this study were approved by the Institutional Animal Care and Use Committee of University of Texas Health San Antonio.

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Hashem, J., Hu, M., Zhang, J. et al. Inhibition of 2-Arachidonoylglycerol Metabolism Alleviates Neuropathology and Improves Cognitive Function in a Tau Mouse Model of Alzheimer’s Disease. Mol Neurobiol 58, 4122–4133 (2021). https://doi.org/10.1007/s12035-021-02400-2

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Keywords

  • 2-Arachidonoylglycerol
  • Monoacylglycerol lipase
  • Alzheimer’s disease
  • Neuroinflammation
  • Tauopathies
  • Cognition