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• W2144657811 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. 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. Inactivation of MAGL reduces Aβ plaques and BACE1 expression in AD mice MAGL inhibition decreases neuroinflammation and neurodegeneration MAGL inhibition maintains integrity of hippocampal synaptic structure and function MAGL inhibition improves synaptic plasticity and learning and memory in AD mice Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function, and loss of memory in association with widespread neuronal death. Over 5.4 million people in the United States and 36 million people worldwide suffer with AD in its various stages. Unfortunately, the few agents that are currently approved by the Food and Drug Administration for treatment of AD have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression or prevention. Thus, there is a great public health need to discover or identify novel therapeutic targets for prevention and treatment of AD. Monoacylglycerol lipase (MAGL) is an enzyme belonging to the serine hydrolase superfamily metabolizing lipids (Labar et al., 2010Labar G. Wouters J. Lambert D.M. A review on the monoacylglycerol lipase: at the interface between fat and endocannabinoid signalling.Curr. Med. Chem. 2010; 17: 2588-2607Crossref PubMed Scopus (96) Google Scholar; Zechner et al., 2009Zechner R. Kienesberger P.C. Haemmerle G. Zimmermann R. Lass A. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores.J. Lipid Res. 2009; 50: 3-21Crossref PubMed Scopus (412) Google Scholar), but its most striking role unveiled within this decade is in hydrolyzing the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), resulting in the release of the free fatty acid arachidonic acid (AA), a precursor of eicosanoids, and glycerol (Dinh et al., 2002Dinh T.P. Carpenter D. Leslie F.M. Freund T.F. Katona I. Sensi S.L. Kathuria S. Piomelli D. Brain monoglyceride lipase participating in endocannabinoid inactivation.Proc. Natl. Acad. Sci. USA. 2002; 99: 10819-10824Crossref PubMed Scopus (1141) Google Scholar; Blankman et al., 2007Blankman J.L. Simon G.M. Cravatt B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.Chem. Biol. 2007; 14: 1347-1356Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar; Labar et al., 2010Labar G. Wouters J. Lambert D.M. A review on the monoacylglycerol lipase: at the interface between fat and endocannabinoid signalling.Curr. Med. Chem. 2010; 17: 2588-2607Crossref PubMed Scopus (96) Google Scholar; Long et al., 2009aLong J.Z. Li W. Booker L. Burston J.J. Kinsey S.G. Schlosburg J.E. Pavón F.J. Serrano A.M. Selley D.E. Parsons L.H. et al.Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.Nat. Chem. Biol. 2009; 5: 37-44Crossref PubMed Scopus (759) Google Scholar, Long et al., 2009bLong J.Z. Nomura D.K. Cravatt B.F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.Chem. Biol. 2009; 16: 744-753Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). This is evidenced by the observations where inhibition of MAGL by a selective and potent inhibitor JZL184 dramatically elevates brain levels of 2-AG and decreases levels of AA and AA-derived prostaglandins (Blankman et al., 2007Blankman J.L. Simon G.M. Cravatt B.F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.Chem. Biol. 2007; 14: 1347-1356Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar; Long et al., 2009aLong J.Z. Li W. Booker L. Burston J.J. Kinsey S.G. Schlosburg J.E. Pavón F.J. Serrano A.M. Selley D.E. Parsons L.H. et al.Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.Nat. Chem. Biol. 2009; 5: 37-44Crossref PubMed Scopus (759) Google Scholar, Long et al., 2009bLong J.Z. Nomura D.K. Cravatt B.F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.Chem. Biol. 2009; 16: 744-753Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar; Nomura et al., 2011Nomura D.K. Morrison B.E. Blankman J.L. Long J.Z. Kinsey S.G. Marcondes M.C. Ward A.M. Hahn Y.K. Lichtman A.H. Conti B. Cravatt B.F. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.Science. 2011; 334: 809-813Crossref PubMed Scopus (530) Google Scholar). 2-AG functions as a retrograde messenger in regulation or modulation of synaptic transmission and plasticity (Alger, 2009Alger B.E. Endocannabinoid signaling in neural plasticity.Curr Top Behav Neurosci. 2009; 1: 141-172Crossref PubMed Scopus (20) Google Scholar; Heifets and Castillo, 2009Heifets B.D. Castillo P.E. Endocannabinoid signaling and long-term synaptic plasticity.Annu. Rev. Physiol. 2009; 71: 283-306Crossref PubMed Scopus (367) Google Scholar; Kano et al., 2009Kano M. Ohno-Shosaku T. Hashimotodani Y. Uchigashima M. Watanabe M. Endocannabinoid-mediated control of synaptic transmission.Physiol. Rev. 2009; 89: 309-380Crossref PubMed Scopus (1117) Google Scholar), exhibits anti-inflammatory and neuroprotective properties (Arevalo-Martin et al., 2010Arevalo-Martin A. Garcia-Ovejero D. Molina-Holgado E. The endocannabinoid 2-arachidonoylglycerol reduces lesion expansion and white matter damage after spinal cord injury.Neurobiol. Dis. 2010; 38: 304-312Crossref PubMed Scopus (26) Google Scholar; Bisogno and Di Marzo, 2010Bisogno T. Di Marzo V. Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders.CNS Neurol. Disord. Drug Targets. 2010; 9: 564-573Crossref PubMed Scopus (123) Google Scholar; Centonze et al., 2007Centonze D. Finazzi-Agrò A. Bernardi G. Maccarrone M. The endocannabinoid system in targeting inflammatory neurodegenerative diseases.Trends Pharmacol. Sci. 2007; 28: 180-187Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar; Chen et al., 2011Chen X. Zhang J. Chen C. Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults.Neuroscience. 2011; 178: 159-168Crossref PubMed Scopus (92) Google Scholar; Panikashvili et al., 2001Panikashvili D. Simeonidou C. Ben-Shabat S. Hanus L. Breuer A. Mechoulam R. Shohami E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury.Nature. 2001; 413: 527-531Crossref PubMed Scopus (640) Google Scholar, Panikashvili et al., 2005Panikashvili D. Mechoulam R. Beni S.M. Alexandrovich A. Shohami E. CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition.J. Cereb. Blood Flow Metab. 2005; 25: 477-484Crossref PubMed Scopus (158) Google Scholar; Scotter et al., 2010Scotter E.L. Abood M.E. Glass M. The endocannabinoid system as a target for the treatment of neurodegenerative disease.Br. J. Pharmacol. 2010; 160: 480-498Crossref PubMed Scopus (139) Google Scholar; Zhang and Chen, 2008Zhang J. Chen C. Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation.J. Biol. Chem. 2008; 283: 22601-22611Crossref PubMed Scopus (100) Google Scholar), and promotes neurogenesis (Gao et al., 2010Gao Y. Vasilyev D.V. Goncalves M.B. Howell F.V. Hobbs C. Reisenberg M. Shen R. Zhang M.Y. Strassle B.W. Lu P. et al.Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice.J. Neurosci. 2010; 30: 2017-2024Crossref PubMed Scopus (361) Google Scholar). Prostaglandins have been long known as important mediators in synaptic plasticity, inflammatory response and neurodegenerative diseases such as AD (Chen et al., 2002Chen C. Magee J.C. Bazan N.G. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity.J. Neurophysiol. 2002; 87: 2851-2857PubMed Google Scholar; Hein and O'Banion, 2009Hein A.M. O'Banion M.K. Neuroinflammation and memory: the role of prostaglandins.Mol. Neurobiol. 2009; 40: 15-32Crossref PubMed Scopus (133) Google Scholar; Hensley, 2010Hensley K. Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation.J. Alzheimers Dis. 2010; 21: 1-14PubMed Google Scholar). Recent evidence shows that a large proportion of prostaglandins derives from metabolites of 2-AG by MAGL (Nomura et al., 2011Nomura D.K. Morrison B.E. Blankman J.L. Long J.Z. Kinsey S.G. Marcondes M.C. Ward A.M. Hahn Y.K. Lichtman A.H. Conti B. Cravatt B.F. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.Science. 2011; 334: 809-813Crossref PubMed Scopus (530) Google Scholar). This means that MAGL is crucial in regulating endocannabinoid and prostaglandin signaling that tunes neuroinflammatory and neurodegenerative processes in response various assaults in the brain. Indeed, it has been demonstrated that pharmacological or genetic inhibition of MAGL suppresses neuroinflammation, prevents neurodegeneration against harmful insults, enhances long-term synaptic plasticity, and improves spatial learning through cannabinoid receptor type 1 (CB1R)-mediated mechanisms (Chen et al., 2011Chen X. Zhang J. Chen C. Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults.Neuroscience. 2011; 178: 159-168Crossref PubMed Scopus (92) Google Scholar; Pan et al., 2009Pan B. Wang W. Long J.Z. Sun D. Hillard C.J. Cravatt B.F. Liu Q.S. Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances retrograde endocannabinoid signaling.J. Pharmacol. Exp. Ther. 2009; 331: 591-597Crossref PubMed Scopus (132) Google Scholar; Du et al., 2011Du H. Chen X. Zhang J. Chen C. Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ.Br. J. Pharmacol. 2011; 163: 1533-1549Crossref PubMed Scopus (93) Google Scholar). Most recent studies show that MAGL inactivation suppresses endotoxin lipopolysaccharide (LPS)-induced neuroinflammation and prevents neurodegeneration in a mouse model of Parkinson's disease by decreasing AA and its downstream proinflammatory prostaglandins (Nomura et al., 2011Nomura D.K. Morrison B.E. Blankman J.L. Long J.Z. Kinsey S.G. Marcondes M.C. Ward A.M. Hahn Y.K. Lichtman A.H. Conti B. Cravatt B.F. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.Science. 2011; 334: 809-813Crossref PubMed Scopus (530) Google Scholar). These previous studies suggest an important role of MAGL in maintaining homeostasis of brain function and keeping inflammatory response in check. Here we show that inhibition of MAGL significantly reduces neuropathology and improves synaptic and cognitive function in 5XFAD APP transgenic mice, a mouse model of AD (Oakley et al., 2006Oakley H. Cole S.L. Logan S. Maus E. Shao P. Craft J. Guillozet-Bongaarts A. Ohno M. Disterhoft J. Van Eldik L. et al.Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.J. Neurosci. 2006; 26: 10129-10140Crossref PubMed Scopus (2041) Google Scholar), suggesting that MAGL is a promising therapeutic target for preventing and treating AD. Evidence from human AD and animal model studies supports a role of β-amyloid (Aβ) as the initiator in the etiology and pathogenesis of AD (Walsh and Selkoe, 2004Walsh D.M. Selkoe D.J. Deciphering the molecular basis of memory failure in Alzheimer's disease.Neuron. 2004; 44: 181-193Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar; Ashe and Zahs, 2010Ashe K.H. Zahs K.R. Probing the biology of Alzheimer's disease in mice.Neuron. 2010; 66: 631-645Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). To determine the capability of MAGL inactivation in suppressing production and accumulation of Aβ, we used 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), a highly selective and potent MAGL inhibitor, which robustly elevates the levels of 2-AG and reduces AA in the brain (Long et al., 2009aLong J.Z. Li W. Booker L. Burston J.J. Kinsey S.G. Schlosburg J.E. Pavón F.J. Serrano A.M. Selley D.E. Parsons L.H. et al.Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.Nat. Chem. Biol. 2009; 5: 37-44Crossref PubMed Scopus (759) Google Scholar, Long et al., 2009bLong J.Z. Nomura D.K. Cravatt B.F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.Chem. Biol. 2009; 16: 744-753Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar; Schlosburg et al., 2010Schlosburg J.E. Blankman J.L. Long J.Z. Nomura D.K. Pan B. Kinsey S.G. Nguyen P.T. Ramesh D. Booker L. Burston J.J. et al.Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system.Nat. Neurosci. 2010; 13: 1113-1119Crossref PubMed Scopus (486) Google Scholar),. 5XFAD APP transgenic (TG) mice were used as the animal model of AD. As reported previously (Oakley et al., 2006Oakley H. Cole S.L. Logan S. Maus E. Shao P. Craft J. Guillozet-Bongaarts A. Ohno M. Disterhoft J. Van Eldik L. et al.Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.J. Neurosci. 2006; 26: 10129-10140Crossref PubMed Scopus (2041) Google Scholar; Kimura and Ohno, 2009Kimura R. Ohno M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model.Neurobiol. Dis. 2009; 33: 229-235Crossref PubMed Scopus (211) Google Scholar), these mice rapidly recapitulate major features of AD amyloid pathology. Aβ is observed starting at 2 months of age, and amyloid plaques appear at 4 months of age, and a significant increase in amyloid plaques occurs at 5–6 months of age accompanied with synaptic and cognitive deficits. To determine whether inhibition of MAGL prevents and reduces synthesis of Aβ and deposition of Aβ plaques, we used two dosing regimes to treat TG animals with JZL184 (12 mg/kg, intraperitoneally [i.p.]) three times per week starting at 2 months of age for 16 weeks or starting at 4 months of age for 8 weeks. Brain Aβ was detected at 6 months of age. The rationale for choosing this dosing regime is that JZL184 inhibits MAGL by irreversible active-site carbamoylation and 75% of MAGL is inhibited at a dose of 4 mg/kg and a near-complete blockade of MAGL occurs at a dose of 16 mg/kg (Long et al., 2009aLong J.Z. Li W. Booker L. Burston J.J. Kinsey S.G. Schlosburg J.E. Pavón F.J. Serrano A.M. Selley D.E. Parsons L.H. et al.Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.Nat. Chem. Biol. 2009; 5: 37-44Crossref PubMed Scopus (759) Google Scholar, Long et al., 2009bLong J.Z. Nomura D.K. Cravatt B.F. Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.Chem. Biol. 2009; 16: 744-753Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). As shown in Figures S1 and S2, MAGL inhibition for 16 weeks robustly decreased total Aβ and Aβ42 as well as APP c-terminal fragments (CTFα/β) both in the cortex and hippocampus. We also found that expression of BACE1, the key enzyme for synthesis of neurotoxic Aβ1-42, was significantly suppressed in TG animals that received JZL184 for 16 weeks (Figure S2). Of significance, TG animals treated with JZL184 (12 mg/kg, i.p.) three times per week starting at 4 months of age for 8 weeks also displayed significant decreases in total Aβ, Aβ42, CTFα/β, and BACE1 in both the cortex and hippocampus (Figures 1 and 2), similar to those in animals treated for 16 weeks. These results suggest that inactivation of MAGL for 8 weeks is sufficient to decrease production and deposition of total Aβ and Aβ42 and expression of BACE1.Figure S2MAGL Inactivation Reduces Expression of BACE1 and Production of Aβ in TG Mice, Related to Figure 2Show full caption(A) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the cortex in 6 months old TG and their age-matched WT mice treated with the vehicle and JZL184 for 16 weeks.(B) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from 3 to 5 mice per group. ∗∗p < 0.01 compared with the WT vehicle control; §§p < 0.01 compared with the TG vehicle control.View Large Image Figure ViewerDownload (PPT)Figure 1MAGL Inhibition Reduces Production and Deposition of Aβ in 5XFAD APP TG MiceShow full caption(A and B) Accumulation and deposition of total Aβ (all forms) and Aβ42 in 6-month-old TG and their age-matched WT mice that received the vehicle and JZL184 (12 mg/kg, i.p.) three times per week starting at 4 months of age for 8 weeks. Total Aβ and Aβ42 were detected using immunohistochemistry with antibodies specific for all forms of Aβ (4G8, green) and for Aβ42 (green). Cell nuclei in the sections were stained with DAPI (blue). Scale bars represent 400 μm.(C) Magnification of Aβ plaques in vehicle- and JZL-treated TG mice.(D) Number of total Aβ and Aβ42 plaques in the cortex and hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from five to six mice per group. ∗∗p < 0.01 compared with the vehicle control.See also Figure S1.View Large Image Figure ViewerDownload (PPT)Figure 2MAGL Inhibitor JZL184 Decreases Expression of BACE1 and Production of Aβ in TG MiceShow full caption(A) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the cortex in 6-month-old TG and their age-matched WT mice treated with the vehicle and JZL184 for 8 weeks.(B) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from four to six mice per group.∗∗p < 0.01 compared with the WT vehicle control; #p < 0.05, ##p < 0.01 compared with the TG vehicle control. See also Figure S2.View Large Image Figure ViewerDownload (PPT) (A) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the cortex in 6 months old TG and their age-matched WT mice treated with the vehicle and JZL184 for 16 weeks. (B) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from 3 to 5 mice per group. ∗∗p < 0.01 compared with the WT vehicle control; §§p < 0.01 compared with the TG vehicle control. (A and B) Accumulation and deposition of total Aβ (all forms) and Aβ42 in 6-month-old TG and their age-matched WT mice that received the vehicle and JZL184 (12 mg/kg, i.p.) three times per week starting at 4 months of age for 8 weeks. Total Aβ and Aβ42 were detected using immunohistochemistry with antibodies specific for all forms of Aβ (4G8, green) and for Aβ42 (green). Cell nuclei in the sections were stained with DAPI (blue). Scale bars represent 400 μm. (C) Magnification of Aβ plaques in vehicle- and JZL-treated TG mice. (D) Number of total Aβ and Aβ42 plaques in the cortex and hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from five to six mice per group. ∗∗p < 0.01 compared with the vehicle control. See also Figure S1. (A) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the cortex in 6-month-old TG and their age-matched WT mice treated with the vehicle and JZL184 for 8 weeks. (B) Immunoblot analysis of APP, BACE1, CTFβ/α, and Aβ42 in the hippocampus in vehicle- and JZL-treated TG mice. Data are means ± SEM from four to six mice per group. ∗∗p < 0.01 compared with the WT vehicle control; #p < 0.05, ##p < 0.01 compared with the TG vehicle control. See also Figure S2. Neuroinflammation is one of the major pathogenetic mechanisms that in concert lead to synaptic and cognitive deficits in AD. Astrocytes and microglia, which produce proinflammatory cytokines, chemokines, and the complement system, are the characteristic components of the inflammatory response. To determine whether inhibition of MAGL prevents activation of astroglial cells, we determined reactive astrocytes and microglia using specific markers in TG animals that received JZL184 for 8 weeks. We found that JZL184 reduced reactive astroglial cells in the cortex and hippocampus of TG mice (Figures 3A–3C ), indicating that neuroinflammation was suppressed when MAGL is inhibited. Neurodegenerative changes are an important feature of neuropathology in AD. To determine whether MAGL inhibition reduces neurodegeneration, we stained brain slices with Fluoro-Jade C (FJC, a neurodegenerative marker) in TG animals that received JZL184 and observed that FJC positive neurons in the brain were significantly decreased in both TG mice treated with JZL184 for 16 weeks (Figures 3D and 3E1) and 8 weeks (Figure 3E2). It is generally accepted that deficits in structure and function of synapses are primary events in the early stages of AD and synaptic loss has been correlated with cognitive deficits in AD patients (DeKosky and Scheff, 1990DeKosky S.T. Scheff S.W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity.Ann. Neurol. 1990; 27: 457-464Crossref PubMed Scopus (1701) Google Scholar; Selkoe, 2002Selkoe D.J. Alzheimer's disease is a synaptic failure.Science. 2002; 298: 789-791Crossref PubMed Scopus (3438) Google Scholar). To determine whether MAGL inhibition prevents abnormality of hippocampal synapses in AD animals, we detected morphology of dendritic spines of pyramidal neurons in the CA1 region and granule neurons in the dentate gyrus using a two-photon laser scanning microscope in TG mice crossed bred with principal neuron-specific GFP transgenic mice (Feng et al., 2000Feng G. Mellor R.H. Bernstein M. Keller-Peck C. Nguyen Q.T. Wallace M. Nerbonne J.M. Lichtman J.W. Sanes J.R. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP.Neuron. 2000; 28: 41-51Abstract Full Text Full Text PDF PubMed Scopus (2451) Google Scholar). As seen in Figures 4B and 4C, the density of total and mushroom dendritic spines of both hippocampal CA1 pyramidal neurons and dentate granule neurons were significantly reduced in TG mice when compared to that in wild-type (WT) animals. However, the abnormality of spines was prevented in TG animals that received JZL184 for 8 weeks (Figures 4B and 4C). In particular, the reduced density of mushroom spines was returned to the control level in JZL184-treated TG mice. Interestingly, the density of mushroom spines, where AMPA and NMDA receptors are primarily expressed and important for synaptic plasticity, was increased in WT animals treated with JZL184 when compared with vehicle-treated WT mice (Figures 4B and 4C), suggesting that MAGL inactivation promotes neurite growth in dendrites. AMPA and NMDA receptors in excitatory synapses are critical for synaptic transmission and plasticity. To determine whether MAGL inhibition diminishes the impaired expression of glutamate AMPA and/or NMDA receptor subunits in AD (Almeida et al., 2005Almeida C.G. Tampellini D. Takahashi R.H. Greengard P. Lin M.T. Snyder E.M. Gouras G.K. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.Neurobiol. Dis. 2005; 20: 187-198Crossref PubMed Scopus (330) Google Scholar; Battaglia et al., 2007Battaglia F. Wang H.Y. Ghilardi M.F. Gashi E. Quartarone A. Friedman E. Nixon R.A. Cortical plasticity in Alzheimer's disease in humans and rodents.Biol. Psychiatry. 2007; 62: 1405-1412Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar; Hsieh et al., 2006Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.Neuron. 2006; 52: 831-843Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar), we detected expression of GluR1, GluR2, NR1, NR2A, and NR2B in WT and TG animals. As shown in Figures 4D and S3, expression of GluR1, GluR2, NR2A, and NR2B both in the cortex and hippocampus was significantly reduced in TG mice, but the reduction was prevented in TG animals treated with JZL184 for 8 or 16 weeks. In particular, we observed that the expression levels of these subunits were greater in both JZL184-treated TG and WT animals compared to WT vehicle controls (Figure 4D). This observation may underlie enhanced long-term potentiation (LTP) and improved spatial learning in MAGL knockout mice (Pan et al., 2011Pan B. Wang W. Zhong P. Blankman J.L. Cravatt B.F. Liu Q.S. Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice.J. Neurosci. 2011; 31: 13420-13430Crossref PubMed Scopus (124) Google Scholar). We also found that decreased expression of PSD-95, a postsynaptic marker, in TG mice was rescued by inhibition of MAGL (Figure S3). To determine whether MAGL inhibition, which prevented decreases in expression of hippocampal glutamate receptor subunits in TG animals, keeps functional normality of the glutamatergic synaptic transmission in TG animals, we recorded spontaneous excitatory postsynaptic currents (sEPSCs) in hippocampal CA1 pyramidal neurons. As shown in Figure 4E, both frequency and amplitude of sEPSCs in TG mice were significantly reduced when compared to those in WT animals, consistent with the previous reports by others (Ting et al., 2007Ting J.T. Kelley B.G. Lambert T.J. Cook D.G. Sullivan J.M. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms.Proc. Natl. Acad. Sci. USA. 2007; 104: 353-358Crossref PubMed Scopus (111) Google Scholar). Inhibition of MAGL resulted in increase in the amplitude of sEPSCs both in TG and WT animals, but not in the frequency. The reduced frequency and amplitude of sEPSCs are likely associated with the loss of presynaptic terminals and/or vesicular release at terminals (Mucke et al., 2000Mucke L. Masliah E. Yu G.Q. Mallory M. Rockenstein E.M. Tatsuno G. Hu K. Kholodenko D. Johnson-Wood K. McConlogue L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.J. Neurosci. 2000; 20: 4050-4058Crossref PubMed Google Scholar; Nimmrich and Ebert, 2009Nimmrich V. Ebert U. Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid.Rev. Neurosci. 2009; 20: 1-12Crossref PubMed Scopus (118) Google Scholar) and decreased expression of postsynaptic glutamate receptor subunits in Aβ over-produced animals (Almeida et al., 2005Almeida C.G. Tampellini D. Takahashi R.H. Greengard P. Lin M.T. Snyder E.M. Gouras G.K. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses.Neurobiol. Dis. 2005; 20: 187-198Crossref PubMed Scopus (330) Google Scholar; Battaglia et al., 2007Battaglia F. Wang H.Y. Ghilardi M.F. Gashi E. Quartarone A. Friedman E. Nixon R.A. Cortical plasticity in Alzheimer's disease in" @default.
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• W2144657811 cites W1584834830 @default.
• W2144657811 cites W1604823664 @default.
• W2144657811 cites W1979203254 @default.
• W2144657811 cites W1986435336 @default.
• W2144657811 cites W1987131861 @default.
• W2144657811 cites W1996536154 @default.
• W2144657811 cites W2006214613 @default.
• W2144657811 cites W2006338497 @default.
• W2144657811 cites W2011335492 @default.
• W2144657811 cites W2012624148 @default.
• W2144657811 cites W2014483271 @default.
• W2144657811 cites W2015079598 @default.
• W2144657811 cites W2025563134 @default.
• W2144657811 cites W2026387596 @default.
• W2144657811 cites W2029471635 @default.
• W2144657811 cites W2030777873 @default.
• W2144657811 cites W2032715817 @default.
• W2144657811 cites W2035768389 @default.
• W2144657811 cites W2051554315 @default.
• W2144657811 cites W2054388625 @default.
• W2144657811 cites W2055309785 @default.
• W2144657811 cites W2055651091 @default.
• W2144657811 cites W2056198220 @default.
• W2144657811 cites W2058805663 @default.
• W2144657811 cites W2066448413 @default.
• W2144657811 cites W2080124845 @default.
• W2144657811 cites W2086684657 @default.
• W2144657811 cites W2091646105 @default.
• W2144657811 cites W2095532816 @default.
• W2144657811 cites W2102260997 @default.
• W2144657811 cites W2106537627 @default.
• W2144657811 cites W2109727228 @default.
• W2144657811 cites W2109913391 @default.
• W2144657811 cites W2116562654 @default.
• W2144657811 cites W2120367130 @default.
• W2144657811 cites W2126304984 @default.
• W2144657811 cites W2127624416 @default.
• W2144657811 cites W2127810309 @default.
• W2144657811 cites W2128401893 @default.
• W2144657811 cites W2137004069 @default.
• W2144657811 cites W2141551684 @default.
• W2144657811 cites W2141753787 @default.
• W2144657811 cites W2153438496 @default.
• W2144657811 cites W2156326104 @default.
• W2144657811 cites W2159267312 @default.
• W2144657811 cites W2159586025 @default.
• W2144657811 cites W2163953252 @default.
• W2144657811 cites W2165151662 @default.
• W2144657811 cites W2166267133 @default.
• W2144657811 cites W2168334242 @default.
• W2144657811 cites W2170644095 @default.
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