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Open Access 01-12-2015 | Short report

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells

Authors: Rea Pihlaja, Jatta Takkinen, Olli Eskola, Jenni Vasara, Francisco R López-Picón, Merja Haaparanta-Solin, Juha O Rinne

Published in: Journal of Neuroinflammation | Issue 1/2015

Abstract

Background

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer’s disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.

Findings

Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [¹⁸ F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ₄₂ had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.

Conclusions

JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC. Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer’s disease. Neurobiol Aging. 2012;33:1329–42.CrossRefPubMed

Zhang W, Bai M, Xi Y, Hao J, Zhang Z, Su C, et al. Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice. Neurobiol Aging. 2012;33:2661–77.CrossRefPubMed

Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease - a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2:a006346.CrossRefPubMedCentralPubMed

Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334:809–13.CrossRefPubMedCentralPubMed

Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, et al. Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep. 2012;2:1329–39.CrossRefPubMedCentralPubMed

Piro JR, Benjamin DI, Duerr JM, Pi Y, Gonzales C, Wood KM, et al. A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer’s disease. Cell Rep. 2012;1:617–23.CrossRefPubMedCentralPubMed

Long JZ, Nomura DK, Cravatt BF. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem Biol. 2009;16:744–53.CrossRefPubMedCentralPubMed

Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70.CrossRefPubMed

Wadsworth H, Jones PA, Chau WF, Durrant C, Fouladi N, Passmore J, et al. [¹⁸ F]GE-180: a novel fluorine-18 labelled PET tracer for imaging Translocator protein 18 kDa (TSPO). Bioorg Med Chem Lett. 2012;22:1308–13.CrossRefPubMed

10.

Pihlaja R, Koistinaho J, Kauppinen R, Sandholm J, Tanila H, Koistinaho M. Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes. Glia. 2011;59:1643–57.CrossRefPubMed

11.

Dineley KT, Xia X, Bui D, Sweatt JD, Zheng H. Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem. 2002;277:22768–80.CrossRefPubMed

12.

He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol. 2007;178:829–41.CrossRefPubMedCentralPubMed

13.

Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Aβ causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron. 2005;45:675–88.CrossRefPubMed

14.

Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–7.CrossRefPubMed

15.

Tampellini D, Magrané J, Takahashi RH, Li F, Lin MT, Almeida CG, et al. Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem. 2007;282:18895–906.CrossRefPubMed

16.

Moussaud S, Draheim HJ. A new method to isolate microglia from adult mice and culture them for an extended period of time. J Neurosci Methods. 2010;187:243–53.CrossRefPubMed

17.

Pihlaja R, Koistinaho J, Malm T, Sikkilä H, Vainio S, Koistinaho M. Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer’s disease. Glia. 2008;56:154–63.CrossRefPubMed

18.

Dahlgren KN, Manelli AM, Stine Jr WB, Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002;277:32046–53.CrossRefPubMed

Title: Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells
Authors: Rea Pihlaja
Jatta Takkinen
Olli Eskola
Jenni Vasara
Francisco R López-Picón
Merja Haaparanta-Solin
Juha O Rinne
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-015-0305-9

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Springer Medicine

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells

Abstract

Background

Findings

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Findings

Conclusions

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