β-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-α, PPAR-γ and TRPV1, but not CB₁ or CB₂ receptors.
OBJECTIVE
The endocannabinoid system may regulate glial cell functions and their responses to pathological stimuli, specifically, Alzheimer's disease. One experimental approach is the enhancement of endocannabinoid tone by blocking the activity of degradative enzymes, such as fatty acid amide hydrolase (FAAH).


METHODS
We examined the role of FAAH in the response of astrocytes to the pathologic form of β-amyloid (Aβ). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with Aβ for 8, 24 and 48 h, and their inflammatory responses were quantified by elisa, western-blotting and real-time quantitative-PCR.


RESULTS
FAAH-KO astrocytes were significantly more responsive to Aβ than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-α was also increased in Aβ-exposed KO astrocytes compared with that in WTs. These effects were accompanied by a differential pattern of activation of signalling cascades involved in mediating inflammatory responses, such as ERK1/2, p38MAPK and NFκB. PPAR-α and PPAR-γ as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB₁ or CB₂ receptors, mediate some of the differential changes observed in Aβ-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to Aβ. In contrast, exogenous addition of several acylethanolamides (anandamide, palmitoylethanolamide and oleoylethanolamide) induced an antiinflammatory response.


CONCLUSIONS
The genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against Aβ in a process involving PPAR-α, PPAR-γ and TRPV1 receptors.
Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain.
Cristina
C
Benito
Rosa María
RM
Tolón
Ana Isabel
AI
Castillo
Lourdes
L
Ruiz-Valdepeñas
José Antonio
JA
Martínez-Orgado
Francisco Javier
FJ
Fernández-Sánchez
Carmen
C
Vázquez
Benjamin F
BF
Cravatt
Julián
J
Romero
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D016229:Amyloid beta-Peptides; D051546:Cyclooxygenase 2; D016207:Cytokines; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D052247:Nitric Oxide Synthase Type II; D047493:PPAR alpha; D047495:PPAR gamma; D010446:Peptide Fragments; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C571431:Cnr2 protein, mouse; C493921:TRPV1 protein, mouse; C075222:amyloid beta-protein (1-42); C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse