title: Normal aging in rats and pathological aging in human Alzheimer's disease decrease FAAH activity: modulation by cannabinoid agonists.
abstract: Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 8000 Bahía Blanca, Argentina.
authors.forename: A C
authors.initials: AC
authors.lastname: Pascual
authors.affiliation: Department of Cellular, Molecular and Developmental Neuroscience and CIBERNED, Cajal Institute, CISC, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Martín-Moreno
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 8000 Bahía Blanca, Argentina.
authors.forename: N M
authors.initials: NM
authors.lastname: Giusto
authors.affiliation: Department of Cellular, Molecular and Developmental Neuroscience and CIBERNED, Cajal Institute, CISC, Madrid, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: de Ceballos
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 8000 Bahía Blanca, Argentina. Electronic address: pasquare@criba.edu.ar.
authors.forename: S J
authors.initials: SJ
authors.lastname: Pasquaré
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D016229:Amyloid beta-Peptides; D001095:Arachidonic Acids; D001549:Benzamides; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C078814:anandamide
keywords: Aging; Alzheimer's disease; Anandamide; Cannabinoid receptors; Central nervous system; Fatty acid amide hydrolase