Epigenetic Regulation of Fatty Acid Amide Hydrolase in Alzheimer Disease

D’Addario, Claudio; Francesco, Andrea Di; Arosio, Beatrice; Gussago, Cristina; Dell’Osso, Bernardo; Bari, Monica; Galimberti, Daniela; Scarpini, Elio; Altamura, Alfredo Carlo; Mari, Daniela; Maccarrone, Mauro

doi:10.1371/journal.pone.0039186

Cited by 66 publications

(46 citation statements)

References 54 publications

(73 reference statements)

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“…This study was followed by an investigation of mRNA expression in the blood of subjects with AD in which expression of CNR2 was associated with AD and correlated with measures of cognitive impairment (8). More recently, a study of mRNA expression and epigenic regulation of endocannabinoid system components in the periphery of AD patients relative to controls revealed an increase in the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), an increase in FAAH protein levels, an increase in FAAH activity and a reduction in DNA methylation at the FAAH gene promoter (9).…”

Section: Introductionmentioning

confidence: 99%

CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer’s Disease

Koppel

Vingtdeux

Marambaud

et al. 2013

Mol Med

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The endocannabinoid CB 2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB 2 receptor system on AD pathology, a colony of mice with a deleted CB 2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB 2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2 -/-(Cnr2 tm1Dgen /J) mice to produce a colony of J20 CNR2 +/+ and J20 CNR2 -/-mice. Seventeen J20 CNR2 +/+ mice (12 females, 5 males) and 16 J20 CNR2 -/-mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB 2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2 -/-mice relative to CNR2 +/+ mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2 -/-mice. Total tau was significantly suppressed in J20 CNR2 -/-mice relative to J20 CNR2 +/+ mice. The results confirm the constitutive role of the CB 2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB 2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

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Section: Introductionmentioning

confidence: 99%

CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer’s Disease

Koppel

Vingtdeux

Marambaud

et al. 2013

Mol Med

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“…The relative abundance of each mRNA species was assessed by qRT-PCR, using QuantiFast Multiplex PCR Kit (Qiagen) on a DNA Engine Opticon 2 Continuous Fluorescence Detection System (MJ Research). The amplification programme was as follow: 95°C for 2 min, 50 cycles at 95°C for 10 s and 60°C for 30 s. PCR was also performed for the nonCpG-containing region of myoD, that served as a control gene (D'Addario et al, 2012). One microlitre of bisulfite-treated DNA was used for amplification in triplicate in a 20 μL reaction solution containing 10 μL of QuantiFast SYBR Green PCR (Qiagen) and 10 pmol of each primer.…”

Section: Analysis Of Dna Methylation By Methylation-specific Primer Rmentioning

confidence: 99%

Epigenetic control of skin differentiation genes by phytocannabinoids

Pucci

Rapino

Francesco

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEEndocannabinoid signalling has been shown to have a role in the control of epidermal physiology, whereby anandamide is able to regulate the expression of skin differentiation genes through DNA methylation. Here, we investigated the possible epigenetic regulation of these genes by several phytocannabinoids, plant-derived cannabinoids that have the potential to be novel therapeutics for various human diseases. EXPERIMENTAL APPROACHThe effects of cannabidiol, cannabigerol and cannabidivarin on the expression of skin differentiation genes keratins 1 and 10, involucrin and transglutaminase 5, as well as on DNA methylation of keratin 10 gene, were investigated in human keratinocytes (HaCaT cells). The effects of these phytocannabinoids on global DNA methylation and the activity and expression of four major DNA methyltransferases (DNMT1, 3a, 3b and 3L) were also examined. KEY RESULTSCannabidiol and cannabigerol significantly reduced the expression of all the genes tested in differentiated HaCaT cells, by increasing DNA methylation of keratin 10 gene, but cannabidivarin was ineffective. Remarkably, cannabidiol reduced keratin 10 mRNA through a type-1 cannabinoid (CB1) receptor-dependent mechanism, whereas cannabigerol did not affect either CB1 or CB2 receptors of HaCaT cells. In addition, cannabidiol, but not cannabigerol, increased global DNA methylation levels by selectively enhancing DNMT1 expression, without affecting DNMT 3a, 3b or 3L. CONCLUSIONS AND IMPLICATIONSThese findings show that the phytocannabinoids cannabidiol and cannabigerol are transcriptional repressors that can control cell proliferation and differentiation. This indicates that they (especially cannabidiol) have the potential to be lead compounds for the development of novel therapeutics for skin diseases. AbbreviationsAEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor type I; CB2, cannabinoid receptor type II; CBD, cannabidiol; CBDV, cannabidivarin; CBG, cannabigerol; CPZ, capsazepine; DAGL, diacylglycerol lipase; DNMT, DNA methyltransferase; eCBs, endocannabinoids; ECS, endocannabinoid system; FAAH, fatty acid amide hydrolase; K1, keratin 1; K10, keratin 10; NAPE-PLD, N-acyl-phosphatidylethanolamines-specific phospholipase D; NHEK, normal human epidermal keratinocytes; MAGL, monoacylglycerol lipase; SR141716, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide; SR144528, N-[(1)-endo-1,3,3-trimethy-1-bicyclo [2.2.1]-heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methyl-benzyl)-pyrazole-3-carboxamide; TGase 5, transglutaminase 5; THC, Δ 9-tetrahydrocannbinol; TPA, 12-O-tetradecanoylphorbol 13-acetate; TRPV1, transient receptor potential vanilloid 1 IntroductionEndocannabinoids (eCBs) are lipid mediators derived from membrane precursors and are involved in multiple regulatory functions, both in health and disease (Di Marzo and Petrosino, 2007). The two most important eCBs are N-arachidonylethanolamine ('anandamide', AEA) and 2-arachidonoylglycerol (2-AG) that elicit their a...

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“…We have recently reported a selective increase in 5-lipoxygenase (5-LOX) (Di Francesco et al, 2013) and fatty acid amide hydrolase (FAAH) (D'Addario et al, 2012) gene expression, paralleled by a reduction in DNA methylation at both promoters in LOAD subjects, when compared to non-demented age-and gender-matched healthy subjects. However, 5mC changes at specific loci are not always representative of changes occurring at global levels (Rao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%