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

Abstract

BACKGROUND AND PURPOSEThe 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). EXPERIMENTAL APPROACHWe examined the role of FAAH in the response of astrocytes to the pathologic form of b-amyloid (Ab). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with Ab for 8, 24 and 48 h, and their inflammatory responses were quantified by ELISA, western-blotting and real-time quantitative-PCR. KEY RESULTSFAAH-KO astrocytes were significantly more responsive to Ab than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-a was also increased in Ab-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 NFk B. PPAR-a and PPAR-g as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB1 or CB2 receptors, mediate some of the differential changes observed in Ab-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to Ab. In contrast, exogenous addition of several acylethanolamides (anandamide, palmitoylethanolamide and oleoylethanolamide) induced an antiinflammatory response. CONCLUSIONSThe genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against Ab in a process involving PPAR-a, PPAR-g and TRPV1 receptors.

Enhanced microglial activity in FAAH−/− animals

“…Our finding does not exclude that under more inflammatory conditions than brain-ageing AEA may also influence astrocyte activities. Indeed, astrocytes of FAAH -/-mice were more responsive to amyloid-β as indicated by an increased production of pro-inflammatory cytokines [53] . Nevertheless, pharmacological blockade of FAAH did not change astrocyte reactivity [53] .…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…In addition, beneficial effects of cannabinoids in AD may also be, at least partially, related to the activation of PPAR nuclear receptors for which certain cannabinoids may serve as ligands [88,91], whereas, in the case of some particular cannabinoids (e.g., antioxidant phytocannabinoids), they may exert some more specific effects in relation with AD pathogenesis, for example: 1) by preventing Aβ aggregation, thereby hindering plaque formation and reducing the density of neuritic plaques due to inhibition of acetylcholinesterase activity or increased expression of neprilysin, an enzyme in the Aβ degradation cascade [86,[91][92][93][94]; and 2) by inhibiting Aβ-induced tau protein hyperphosphorylation by glycogen synthase kinase-3β [82][83][84]. Some recent studies have also highlighted the interest of targeting endocannabinoid inactivation in AD, through strategies of genetic inactivation [e.g., mice deficient in monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH)] or by inhibiting these enzymes (e.g., JZL184, URB597, respectively) [95][96][97][98]. However, in some cases, these effects were not related to an increased CB 1 R and/or CB 2 R signaling, but to other pathways, for example PPAR signaling, alterations in arachidonic acid, and/or prostaglandin signaling [95,96].…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…The selective activation of either cannabinoid receptor type is beneficial at preserving neuronal cells or preventing microglial activation induced by ␤-amyloid peptides (22,717). The beneficial effects of genetic or pharmacological inactivation of endocannabinoid degradative enzymes were also investigated (61,139,685,878). However, in agreement with the hypothesis that activation of CB1, particularly by 2-AG, might also contribute to some of the cognitive impairments in late stages of the disease, because of maladaptive neuromodulatory effects (603), also CB1 antagonists can produce beneficial effects (546), and a FAAH inhibitor capable of elevating 2-AG levels was shown to ameliorate memory retention loss caused by ␤-amyloid only when administered early after the insult (869).…”