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. Author manuscript; available in PMC: 2013 Jul 19.
Published in final edited form as: Cell Rep. 2012 Jun 21;1(6):617–623. doi: 10.1016/j.celrep.2012.05.001

A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

Justin R Piro 1, Daniel I Benjamin 2, James M Duerr 1, YeQing Pi 1, Cathleen Gonzales 1, Kathleen M Wood 1, Joel W Schwartz 1, Daniel K Nomura 2,*, Tarek A Samad 1,*
PMCID: PMC3715876  NIHMSID: NIHMS376082  PMID: 22813736

Summary

Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer’s disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid βlevels and plaques, in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a heretofore unrecognized role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology, and put forth MAGL inhibitors as a potential next-generation strategy for combatting AD.

Introduction

Neuroinflammation is a fundamental underlying hallmark of Alzheimer’s disease (AD), a debilitating neurodegenerative condition marked by accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of aggregated amyloid β (Aβ) and hyperphosphorylated tau, respectively, leading to progressive cognitive impairment and dementia (Glass et al., 2010). Suppressing inflammation has been shown to reduce AD pathological hallmarks as well as cognitive and behavioral deficits in AD models (Choi and Bosetti, 2009; Liu et al., 2012). Recently, there has been considerable interest in exploring the therapeutic potential of anti-inflammatory agents to prevent, treat, or slow the progression of AD (Aid and Bosetti, 2011; Cunningham and Skelly, 2011).

Ablation of cyclooxygenases (COX) 1 or 2 with non-steroidal anti-inflammatory drugs (NSAIDs) or in COX1 or COX2 knockout mice reduces prostaglandins and suppresses neuroinflammation, concordant with significant improvements in cognitive, behavioral and memory impairments as well as reductions in Aβ plaques and hyperphosphorylated tau in AD mouse models (Choi and Bosetti, 2009; Kotilinek et al., 2008; McKee et al., 2008). Retrospective human epidemiological studies have also demonstrated protective effects or delayed onset of AD upon prolonged NSAID treatment when initiated early or before disease initiation, respectively (Rogers et al., 1993; Szekely et al., 2008) however, NSAIDs have not shown efficacy in AD patients with mild to moderate cognitive impairment (Imbimbo et al., 2010). Other anti-inflammatory strategies have also shown efficacy at reducing pathology in animal models, including treatment with anti-tumor necrosis factor α (TNFα) or interleukin-1β (IL-1β) antibodies (Kitazawa et al., 2011; Shi et al., 2011). Pharmacological intervention based on chronic treatment with COX inhibitors or treatment with anti-cytokine therapies, however, is not ideal for long-term use due to their respective gastrointestinal (COX1-selective), cardiovascular (COX2-selective), or immunosuppressive (anti-cytokine therapies) side-effects (Ng and Chan, 2010; Raychaudhuri et al., 2009). Novel and safer anti-inflammatory strategies are thus required not only to gain a deeper understanding of the role that inflammation plays in AD disease progression, but also to investigate its therapeutic potential in combatting AD.

We have recently discovered that monoacylglycerol lipase (MAGL), an enzyme that terminates the signaling of the anti-inflammatory endocannabinoid signaling lipid 2-arachidonoylglcerol (2-AG) (Long et al., 2009), also controls arachidonic acid (AA) release for the production of pro-inflammatory eicosanoids (which include lipids such as prostaglandins and thromboxanes) in the brain (Nomura et al., 2011). We found that genetic and pharmacological blockade of MAGL not only leads to enhanced endocannabinoid levels, but also reduced prostaglandins in the brain under both basal and inflammatory states.

In this study, we asked whether MAGL inactivation modulates AD pathogenesis in a mouse model of Aβ deposition. We present direct evidence that MAGL inactivation reduces pro-inflammatory prostaglandins and cytokine signaling machinery, and produces profound suppression of neuroinflammation and reductions in Aβ levels and plaque burden.

Results

Metabolomic Profiling of PS1/APP+ AD Mouse Model

To identify dysregulated metabolic networks that underlie AD pathophysiology, we profiled the lipidome of the PS1/APP+ mouse brains, which exhibit an age dependent elevation in Aβ levels and plaque deposition (Fig. S1). Using a combination of targeted and untargeted liquid chromatography/mass spectrometry (LC/MS)-based metabolomic profiling platforms, we identified several classes of lipids that were elevated in the PS1/APP+ mouse brains compared to their wild-type counterparts (Fig. 1A), including monoacylglycerols (MAGs), N-acylethanolamines (NAEs), free fatty acids (FFAs), eicosanoids, phosphatidic acids (PAs), lysophosphatidyl cholines (LPCs), and cholesteryl esters. Among this metabolic signature, we were particularly intrigued by the heightened endocannabinoid and eicosanoid levels in PS1/APP+ brains (Fig. 1A; Table S1). We postulated that the elevated eicosanoid levels in PS1/APP+ mouse brains were driven by MAGL-mediated 2-AG hydrolysis and AA release (Fig. 1B).

Figure 1. A dysregulated endocannabinoid-eicosanoid network in a mouse model of Alzheimer's disease.

Figure 1

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(A) Comparative metabolomic profiling of PS1/APP+ compared to PS1/APP− mouse brain lipidomes measuring levels of endocannabinoids; 2-AG (C20:4 monoacylglycerol (MAG)), anandamide (C20:4 N-acylethanolamines (NAEs)), arachidonic acid (C20:4 free fatty acids (FFAs)) and eicosanoids (prostaglandin E2 (PGE2), PGD2 and thromboxane B2 (TXB2)). Elevations in other MAGs, NAEs, and FFAs, as well as phosphatidic acids (PAs), lysophosphatidyl cholines (LPCs), and cholesteryl esters are also depicted. LPCs, MAGs, and NAEs mass/charge ratios (m/z) are represented as [M+H]. PAs, eicosanoids, and FFAs are represented as [M-H]. Cholesteryl esters are represented as loss of fatty acid and [M+H-H2O]+. Data were obtained from untargeted and multiple reaction monitoring (MRM)-based targeted LC/MS analysis. The data shown in Fig. 1A represents metabolites that are significantly altered (p<0.05) by greater than 1.5-fold in the PS1/APP+ compared to PS1/APP− mouse brain (n=4–5 mice/group) by two-tailed t-test (raw data in Table S1). The y-axis denotes mass over charge ratio (m/z), the x-axis represents retention time on liquid chromatography, and the size of the circles represent relative fold-change of the metabolite between PS1/APP+ compared to wild-type PS1/APP− mouse brain lipidomes. There were no metabolites that were reduced >1.5-fold in PS1/APP+ brains. Data represent only the metabolites that were consistently altered in two separate experiments each including n=4–5 mice/group. (B) MAGL hydrolyzes the endocannabinoid 2-AG to release the dominant source of AA for COX-mediated eicosanoid (e.g. PGE2, PGD2, TXB2) production in the brain. TXB2 is a non-bioactive breakdown product of TXA2. (C) Brain endocannabinoid and eicosanoid levels determined by multiple reaction monitoring (MRM) using a QQQ-LC/MS from Mgll+/+/PS1/APP−, Mgll−/−/PS1/APP−, Mgll+/+/PS1/APP+, Mgll−/−/PS1/APP+ mouse brains. Data are means ± SEM, n=4–8 mice/group for (A) and n=7–8 mice/group for (C). Significance is shown as *p<0.05, **p<0.01 using a linear model with ANOVA.

Genetic Ablation of MAGL Reduces Neuroinflammatory Eicosanoid Levels in the PS1/APP+ AD Mouse Model

To determine whether MAGL contributes to eicosanoid production, neuroinflammation and pathophysiology in the PS1/APP+ mouse brain, we bred MAGL-disrupted (Mgll−/−) (Chanda et al., 2010) and PS1/APP+ transgenic mice (Samaroo et al., 2012) to generate 4 genotypes for our studies: Mgll+/+/PS1/APP−, Mgll+/+/PS1/APP+, Mgll−/−/PS1/APP−, and Mgll−/−/PS1/APP+. We found that Mgll−/−/PS1/APP− and Mgll−/−/PS1/APP+ mice presented higher levels of the MAGL substrate 2-AG (C20:4 MAG) and dramatically reduced levels of AA (C20:4 FFA), prostaglandins (PGE2 and PGD2), and thromboxane B2 (TXB2) in their brains compared to their Mgll+/+/PS1/APP− and Mgll+/+/ PS1/APP+ counterparts, respectively (Fig. 1C; Table S1). In contrast, the second major endocannabinoid, anandamide (C20:4 NAE), although elevated in PS1/APP+ mouse brains, was not altered upon genetic deficiency of MAGL (Fig. 1C; Table S1). These results show that PS1/APP+ mice have heightened levels of pro-inflammatory prostaglandins that are generated primarily by MAGL-mediated hydrolysis of 2-AG, and that blocking this enzyme can restore prostaglandins to basal or sub-basal levels.

MAGL Inactivation Attenuates Neuroinflammation and Aβ Levels and Plaque Burden in the PS1/APP+ Mouse Brain

We next addressed whether genetic ablation of MAGL reduces neuroinflammation in PS1/APP+ mice. We found that PS1/APP+ mice exhibit significant astrocyte and microglial activation concordant with elevations in pro-inflammatory cytokines and cytokine receptors (Fig. 2A, B, C). Intriguingly, this observed microglial and astrocyte activation was almost completely attenuated in the Mgll−/−/PS1/APP+ mouse brains assessed both by GFAP and Iba-1 immunohistochemical staining and quantitative RT-PCR of GFAP and CD11b, respectively (Fig. 2A,B). Consistent with an anti-inflammatory effect of MAGL inactivation, we also observed dramatic reductions in the inflammatory cytokines IL-1β, IL-6, TNFα, and TNFα receptor II (TNFRII) at the mRNA or active protein level (Fig. 2C). We next assessed whether disruption of MAGL and reduction of neuroinflammation impacts Aβ levels and deposition in the transgenic mouse brain. We found that MAGL inactivation drastically reduced numbers of Aβ plaques (Fig. 3A) and brain levels of total Aβ, as well as the Aβ40, and Aβ42 amyloidogenic peptides (Fig. 3B). Quantitative RT-PCR, conducted to ensure that inactivation of MAGL did not lead to alteration in the transgene expression, revealed no detectible changes in human APP gene expression in the Mgll−/−/PS1/APP+ mice compared to the PS1/APP+ mice (Fig. S2). Collectively, our results show that MAGL inactivation suppresses neuroinflammation in the PS1/APP+ AD mouse model, leading to a substantial reduction in amyloid plaque burden.

Figure 2. MAGL inactivation attenuates gliosis and neuroinflammation in PS1/APP+ mouse brains.

Figure 2

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Immunohistochemical analysis of astrocytes (A) and microglia (B) in Mgll+/+/PS1/APP−, Mgll+/+/PS1/APP+, and Mgll−/−/PS1/APP+ mouse brains determined by GFAP (A) and Iba-1 staining respectively, and by quantitative RT-PCR for GFAP (A) or CD11b (B) mRNA expression in cortical brain. Representative images of n=4–5 mice/group are shown. Scale bars for images are 20 μm. (C) Measurements of pro-inflammatory cytokines and receptors in Mgll+/+/PS1/APP−, Mgll+/+/PS1/APP+, and Mgll−/−/PS1/APP+ mouse brains determined by quantitative RT-PCR of IL-1β, TNFα, and TNFRII gene expression from hippocampus or cortex and ELISA-based protein quantitation for IL-1β, IL-6, and TNFα from soluble proteomes of whole mouse brain. Data are means ± SEM, n=4–5 mice/group. Significance is shown as *p<0.05, **p<0.01 using ANOVA with Tukey-Kramer post-hoc test.

Figure 3. MAGL ablation reduces amyloid plaques in PS1/APP+ mouse brain.

Figure 3

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(A) Quantification of amyloid plaques in Mgll+/+/PS1/APP−, Mgll+/+/PS1/APP+, and Mgll−/− /PS1/APP+ mouse brains determined by thioflavin S staining (Ctx: Cortex; Hipp: Hippocampus). Quantitation of the number of amyloid plaques per section per mouse is shown. Thioflavin S images on the left panel are representative. Scale bars for images represent 400 and 100 μm, respectively, for the left and right panels. (B) Quantitation of total Aβ, Aβ40, and Aβ42 protein levels by DELFIA. Data are means ± SEM, n=4–5 mice/group. Significance is shown as *p<0.05, **p<0.01 using ANOVA with Tukey-Kramer post-hoc test for (A) and two-tailed t-test for (B). See also Figure S1 and Figure S2.

Pharmacological Blockade of MAGL in the PS1/APP+ AD Model

We next asked whether pharmacological inactivation of MAGL in PS1/APP+ mice, with treatment initiated at 6 months well-after the onset of elevated Aβ levels (Fig. S1) and formation of amyloid plaques, recapitulates the metabolic and anti-inflammatory effects observed with genetic deficiency of MAGL. We found that subchronic MAGL blockade with the selective inhibitor JZL184 (40 mg/kg ip, once per day over 16 days) in PS1/APP+ mice, produced elevations in 2-AG and substantial reductions in AA, pro-inflammatory prostaglandins, and thromboxanes (Fig. 4A). We found that JZL184 also significantly reduced pro-inflammatory cytokine levels in PS1/APP+ mouse brains (Fig. 4B, 4C). To investigate whether these eicosanoid and cytokine-lowering anti-inflammatory effects of the MAGL inhibitors were due to enhancements in 2-AG signaling versus an attenuation of eicosanoid production, we included a treatment arm in which JZL184 was co-administered with cannabinoid receptor type 1 and 2 (CB1 and CB2) antagonists, rimonabant and AM630 (3 mg/kg ip), respectively. We found that the reductions in both pro-inflammatory prostaglandins and cytokines were not reversed upon treatment with cannabinoid receptor antagonists (Fig. 4B), suggesting that the anti-inflammatory effects observed are mediated primarily by reductions in AA levels and prostaglandin signaling, rather than heightened endocannabinoid action.

Figure 4. Pharmacological inactivation of MAGL reduces eicosanoids and lowers inflammatory cytokine levels.

Figure 4

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(A, B) Endocannabinoid and eicosanoid (A) and inflammatory cytokine (B) levels in the brains of PS1/APP− and PS1/APP+ mice treated, starting at 6 months, with either vehicle, JZL184 (40 mg/kg ip), or co-administration of the CB1 and CB2 antagonists, rimonabant (RIM) (3 mg/kg) and AM 630 (3 mg/kg ip), respectively, once per day over 16 days. Endocannabinoid and eicosanoid levels were determined by MRM-based targeted LC/MS analysis and raw data is presented in Table S1. Inflammatory cytokines were quantitated using ELISA from soluble proteomes from hemi-brains. Data are means ± SEM, n=4–8 mice/group. Significance is shown as *p<0.05, **p<0.01using a linear model ANOVA with no correction for multiplicity because of small sample sizes (A) and an ANOVA with Tukey-Kramer post-hoc test for (B).

Discussion

One of the common hallmarks of neurodegenerative diseases, including AD, is chronic and persistent neuroinflammation which in most cases is involved in exacerbating neuronal loss and disease pathology (Glass et al., 2010). Anti-inflammatory strategies have thus been proposed as an attractive approach towards combatting AD (Glass et al., 2010). In this study, we reveal a heretofore unrecognized neuroprotective role of MAGL inactivation as a novel strategy for quelling neuroinflammation and amyloidogenesis that subserves AD.

Several reports have shown that select patterns of microglial activation can lead to phagocytosis and clearance of Aβ plaques in mouse models of AD (Jantzen et al., 2002; Lemere and Masliah, 2010; Stahl et al., 2006). In contrast, our results show that reducing neuroinflammation in the PS1/APP+ transgenic AD mouse model leads to a dramatic decrease in brain amyloid plaques. Our results are supported by multiple studies showing that inactivation of the cyclooxygenases or directly blocking cytokine action with antibodies improves memory function and reduces neuroinflammation and amyloid plaques in mouse AD models (Choi and Bosetti, 2009; Kitazawa et al., 2011; McKee et al., 2008; Shi et al., 2011).

Despite considerable evidence associating neuroinflammation to AD pathophysiology (Glass et al., 2010), the precise mechanisms by which it affects Aβ plaques or AD disease progression are not as well understood. One possible mechanism is the inflammatory regulation of β–secretase (BACE1), the protease that cleaves APP to form Aβ, which possesses an NFκB site in its promoter and is upregulated upon inflammatory stimuli (Chen et al., 2011; Sastre et al., 2008). Anti-inflammatory agents such as NSAIDs and peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to reduce the expression and activity of β–secretase and lower Aβ secretion (Sastre et al., 2003).

Earlier studies have implicated phospholipases, such as cPLA2, as the primary driver for AA release for prostaglandin synthesis (Bonventre et al., 1997). We recently discovered that, although cPLA2 does contribute to a significant portion of pro-inflammatory prostaglandins, MAGL contributes the majority of AA for eicosanoid synthesis in the brain both basally and under the lipopolysaccharide-paradigm of neuroinflammation (Nomura et al., 2011). Moreover, genetic deletion of diacylglycerol lipase (DAGL), the enzyme that synthesizes 2-AG, leads to reduction in brain AA levels (Gao et al., 2010), further supporting a role for endocannabinoid metabolism as a source for brain AA. Nevertheless, genetic and pharmacological ablation of cPLA2 has also been shown to ameliorate cognitive deficits and reduce brain eicosanoid levels in APP transgenic mice (Sanchez-Mejia et al., 2008). These results collectively suggest that both MAGL and cPLA2 may contribute to the generation of AA for prostaglandin production in AD.

We show here that pharmacological blockade of MAGL over a 16 day dosing regimen raises endocannabinoid levels and lowers prostaglandin production, recapitulating the eicosanoid and cytokine-lowering effects observed with genetic deletion of MAGL. We found, however, that cannabinoid receptor signaling is likely not involved in lowering MAGL-driven neuroinflammation in PS1/APP+ mice, despite previous studies showing neuroprotective benefits derived from both enhancing cannabinoid effects or lowering eicosanoid levels in AD (Aid and Bosetti, 2011; Bisogno and Di Marzo, 2010; Martin Moreno et al., 2012). The lack of cannabinoid-mediated effects in our study may be due to functional desensitization of the cannabinoid system that results from chronic and complete MAGL blockade (Schlosburg et al., 2010). It would therefore be of future interest to test whether partial MAGL blockade can elicit additive or synergistic benefits against AD by maintaining CB1 signaling and suppressing prostaglandin pathways simultaneously.

Despite their well-documented protective effects when initiated early and taken over prolonged periods (Rogers et al., 1993; Vlad et al., 2008), an issue with NSAIDs has been their lack of efficacy in AD clinical studies (Imbimbo et al., 2010; McGeer and McGeer, 2007). We believe that anti-inflammatory agents may be most beneficial when treatment is initiated during amyloidogenesis but before neuronal loss and synaptic failure, since anti-inflammatory agents will not likely reverse neurodegeneration.

Beyond its anti-inflammatory roles, enhancing endocannabinoid signaling has also been shown to promote neurogenesis and improve memory (Aguado et al., 2005; Galve-Roperh et al., 2007; Pan et al., 2011). In this study, we have not yet formally demonstrated the efficacy of MAGL inhibitors at lowering amyloid plaques or improving memory or behavior. It will thus be of future interest to test whether MAGL inhibitors provide therapeutic efficacy towards these parameters.

Our metabolomic profiling showed altered endocannabinoid and eicosanoid brain metabolism in the PS1/APP+ AD mouse model, alongside alterations in certain phospholipids and cholesteryl esters. Our findings are consistent with previous studies showing that lowering eicosanoids or cholesterol in the brain may have therapeutic benefit in AD (Di Paolo and Kim, 2011; Sanchez-Mejia et al., 2008).

In this study, we find that blocking MAGL substantially reduces neuroinflammation that underlies AD pathogenesis and attenuates amyloidosis, likely through suppressing pro-inflammatory eicosanoid production. Our results thus highlight MAGL inhibitors as an attractive therapeutic strategy for treating AD.

Experimental Procedures

Mice and Chemicals

Mgll−/− mice (Chanda et al., 2010) were crossed with PS1/APP+ transgenic mice (Samaroo et al., 2012) to create the 4 genotypes used in these studies: Mgll+/+/PS1/APP−, Mgll+/+/PS1/APP+, Mgll−/−/PS1/APP−, and Mgll−/−/PS1/APP+. All experiments were conducted in accordance with Pfizer’s IACUC guidelines. The compounds JZL184 and rimonabant were synthesized in the laboratory (Pfizer Inc.). AM 630 was purchased from Tocris Bioscience (Minneapolis, MN).

mRNA Expression of Pro-Inflammatory Cytokines and Receptors

Brains from transgenic or pharmacologically treated animals were dissected and rapidly frozen in liquid nitrogen. Total RNA was isolated from frozen tissues and gene expression was assessed by quantitative RT-PCR.

Metabolomic Analysis

Metabolomic analysis was performed as previously described (Nomura et al., 2011). Briefly, mice were sacrificed by cervical dislocation and brains were removed rapidly (≤ 30 s) and snap frozen in liquid nitrogen.Metabolites were extracted in 3 ml of 1:1 ethyl acetate:hexane and 1 ml PBS. An aliquot of the organic extract was injected onto a triple quadrupole-LC/MS/MS for untargeted and targeted metabolite analysis. We combined data obtained from both of these analytic procedures and have tabulated relative levels of metabolites in Table S1.

Measurement of Pro-inflammatory Cytokine Levels

Cytokines were then measured from soluble brain proteome (25 μg) using the Mouse Inflammatory Cytokines Multi-Analyte ELISArray kit (Qiagen, Valencia, CA) per a modified version of the manufacturer’s instructions. More details are in Supplemental Information.

Immunohistochemistry and plaque quantitation

Four representative slides from each animal were incubated with anti-GFAP (Millipore, USA) or anti-Iba1 (Wako, Japan) to determine the activation of astrocytes or microglia respectively. Sections were also stained with thioflavin S. Multiple equivalent sections across each sample were imaged and thioflavin S+ plaques counted using a computer algorithm developed at Pfizer.

Supplementary Material

01
02. Table S1. Individual biological replicates of LC/MS data.

Provided as an excel spreadsheet

Highlights.

  • MAGL is a major contributor to arachidonic acid pools in the brain.

  • Genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques, in an Alzheimer’s disease (AD) mouse model.

  • Pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling.

  • Our findings reveal a novel role of MAGL in modulating AD etiology by reducing neuroinflammation and amyloidosis. We therefore, put forth MAGL inhibitors as a potential next-generation strategy for combatting AD.

Acknowledgments

We thank Rita Balice-Gordon, Kelly Bales, Xiaoxi Li, members of the Neuroscience Research Unit at Pfizer Global Research and the Nomura laboratory for discussion and critical reading of the manuscript. This work was supported by Pfizer Global Research (JRP, JMD, YP, CG, KMW, JWS, TAS) and the National Institutes of Health (R00DA030908 (DKN, DIB)).

Footnotes

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References

  1. Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzman M, Galve-Roperh I. The endocannabinoid system drives neural progenitor proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2005;19:1704–1706. doi: 10.1096/fj.05-3995fje. [DOI] [PubMed] [Google Scholar]
  2. Aid S, Bosetti F. Targeting cyclooxygenases-1 and -2 in neuroinflammation: Therapeutic implications. Biochimie. 2011;93:46–51. doi: 10.1016/j.biochi.2010.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bisogno T, Di Marzo V. Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders. CNS & neurological disorders drug targets. 2010;9:564–573. doi: 10.2174/187152710793361568. [DOI] [PubMed] [Google Scholar]
  4. Bonventre JV, Huang Z, Taheri MR, O'Leary E, Li E, Moskowitz MA, Sapirstein A. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature. 1997;390:622–625. doi: 10.1038/37635. [DOI] [PubMed] [Google Scholar]
  5. Chanda PK, Gao Y, Mark L, Btesh J, Strassle BW, Lu PM, Piesla MJ, Zhang MY, Bingham B, Uveges A, et al. Monoacylglycerol Lipase Activity Is a Critical Modulator of the Tone and Integrity of the Endocannabinoid System. Molecular pharmacology. 2010;78:996–1003. doi: 10.1124/mol.110.068304. [DOI] [PubMed] [Google Scholar]
  6. Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y, Song W. Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol. 2011:1–14. doi: 10.1017/S1461145711000149. [DOI] [PubMed] [Google Scholar]
  7. Choi SH, Bosetti F. Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging-Us. 2009;1:234–244. doi: 10.18632/aging.100021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cunningham C, Skelly DT. Non-Steroidal Anti-Inflammatory Drugs and Cognitive Function: Are Prostaglandins at the Heart of Cognitive Impairment in Dementia and Delirium ? Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2011 doi: 10.1007/s11481-011-9312-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nature reviews Neuroscience. 2011;12:284–296. doi: 10.1038/nrn3012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Galve-Roperh I, Aguado T, Palazuelos J, Guzman M. The endocannabinoid system and neurogenesis in health and disease. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2007;13:109–114. doi: 10.1177/1073858406296407. [DOI] [PubMed] [Google Scholar]
  11. Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, Shen R, Zhang MY, Strassle BW, Lu P, et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30:2017–2024. doi: 10.1523/JNEUROSCI.5693-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–934. doi: 10.1016/j.cell.2010.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? Frontiers in aging neuroscience. 2010;2 doi: 10.3389/fnagi.2010.00019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, Gordon MN. Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002;22:2246–2254. doi: 10.1523/JNEUROSCI.22-06-02246.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer's disease model. J Immunol. 2011;187:6539–6549. doi: 10.4049/jimmunol.1100620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, et al. Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain : a journal of neurology. 2008;131:651–664. doi: 10.1093/brain/awn008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol. 2010;6:108–119. doi: 10.1038/nrneurol.2009.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J, Heneka MT, Hartmann T, et al. TLR2 Is a Primary Receptor for Alzheimer's Amyloid beta Peptide To Trigger Neuroinflammatory Activation. J Immunol. 2012;188:1098–1107. doi: 10.4049/jimmunol.1101121. [DOI] [PubMed] [Google Scholar]
  19. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavon FJ, Serrano AM, Selley DE, Parsons LH, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nature chemical biology. 2009;5:37–44. doi: 10.1038/nchembio.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Martin Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, Pozo MA, Innamorato NG, Cuadrado A, de Ceballos ML. Prolonged oral Cannabinoid Administration prevents Neuroinflammation, lowers beta-amyloid Levels and improves Cognitive Performance in Tg APP 2576 Mice. Journal of neuroinflammation. 2012;9:8. doi: 10.1186/1742-2094-9-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol Aging. 2007;28:639–647. doi: 10.1016/j.neurobiolaging.2006.03.013. [DOI] [PubMed] [Google Scholar]
  22. McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A. Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res. 2008;1207:225–236. doi: 10.1016/j.brainres.2008.01.095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ng SC, Chan FK. NSAID-induced gastrointestinal and cardiovascular injury. Current opinion in gastroenterology. 2010;26:611–617. doi: 10.1097/MOG.0b013e32833e91eb. [DOI] [PubMed] [Google Scholar]
  24. Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK, Lichtman AH, Conti B, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334:809–813. doi: 10.1126/science.1209200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QS. Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knockout mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011;31:13420–13430. doi: 10.1523/JNEUROSCI.2075-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Raychaudhuri SP, Nguyen CT, Raychaudhuri SK, Gershwin ME. Incidence and nature of infectious disease in patients treated with anti-TNF agents. Autoimmunity reviews. 2009;9:67–81. doi: 10.1016/j.autrev.2009.08.006. [DOI] [PubMed] [Google Scholar]
  27. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M, Mansukhani L, Willson P, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993;43:1609–1611. doi: 10.1212/wnl.43.8.1609. [DOI] [PubMed] [Google Scholar]
  28. Samaroo HD, Opsahl AC, Schreiber J, O'Neill SM, Marconi M, Qian J, Carvajal-Gonzalez S, Tate B, Milici AJ, Bales KR, et al. High throughput object-based image analysis of beta-amyloid plaques in human and transgenic mouse brain. Journal of neuroscience methods. 2012;204:179–188. doi: 10.1016/j.jneumeth.2011.10.003. [DOI] [PubMed] [Google Scholar]
  29. Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y, Halabisky B, Cisse M, Scearce-Levie K, Cheng IH, Gan L, et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat Neurosci. 2008;11:1311–1318. doi: 10.1038/nn.2213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. Journal of Neuroscience. 2003;23:9796–9804. doi: 10.1523/JNEUROSCI.23-30-09796.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sastre M, Walter J, Gentleman SM. Interactions between APP secretases and inflammatory mediators. Journal of neuroinflammation. 2008;5 doi: 10.1186/1742-2094-5-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci. 2010;13:1113–U1111. doi: 10.1038/nn.2616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, Zhu HQ, Zhang QQ, Zhang YD, Xu J. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain research. 2011;1368:239–247. doi: 10.1016/j.brainres.2010.10.053. [DOI] [PubMed] [Google Scholar]
  34. Stahl T, Reimers C, Johne R, Schliebs R, Seeger J. Viral-induced inflammation is accompanied by beta-amyloid plaque reduction in brains of amyloid precursor protein transgenic Tg2576 mice. European Journal of Neuroscience. 2006;24:1923–1934. doi: 10.1111/j.1460-9568.2006.05069.x. [DOI] [PubMed] [Google Scholar]
  35. Szekely CA, Breitner JCS, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, Zandi PP. NSAID use and dementia risk in the cardiovascular health study - Role of APOE and NSAID type. Neurology. 2008;70:17–24. doi: 10.1212/01.wnl.0000284596.95156.48. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

01
NIHMS376082-supplement-01.docx (124.8KB, docx)
02. Table S1. Individual biological replicates of LC/MS data.

Provided as an excel spreadsheet

NIHMS376082-supplement-02.xlsx (36.5KB, xlsx)

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