A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

Abstract

Summary Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer’s disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid βlevels and plaques, in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a heretofore unrecognized role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology, and put forth MAGL inhibitors as a potential next-generation strategy for combatting AD.

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…Recent studies show that the anti-inflammatory and neuroprotective effects by inhibition of MAGL are not mediated by CB1 or by CB2 receptors. 19,21,27 In addition, inhibition of CB1 receptors only partly blocks 2-AG-produced neuroprotective effects in TBI. 22 This suggests that there may be other mechanisms mediating the anti-neuroinflammatory and neuroprotective effects produced by inhibition of 2-AG metabolism.…”

“…5,23,24 Animals were assigned into four groups: (a) naive control, (b) sham control, (c) TBI-vehicle, and (d) TBI-JZL184, a highly selective and potent MAGL inhibitor, which significantly elevates 2-AG levels in the brain. 14,15,19,21,27 JZL184 (10 mg/kg) was injected 30 minutes after each TBI and then once a day for 4 consecutive days ( Figure 1A). The neurologic severity score (NSS), which includes 10 tasks as described previously, 26 was assessed to determine the functional status of animals after rmCHI.…”

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].…”

“…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].…”

“…This is the case, for example, of the upregulation of CB 2 R found in reactive microglial cells surrounding the Aβ plaques, a response found in postmortem brain tissues from patients with AD [87,99], and also in some experimental models [87], which may facilitate the benefits found with compounds selectively targeting this receptor [86,87,90]. However, other effects are better explained as originated by a pharmacological correction of those changes in the endocannabinoid system that may contribute to the progression of AD pathogenesis, for example: 1) the reduction in CB 1 R observed in AD-affected areas [87,100], which may aggravate excitotoxic events that are controlled by CB 1 R signaling, then enhancing neuronal losses; and 2) the elevation of the FAAH enzyme in astrocytes associated with the senile plaques in the postmortem human cortex, which would enhance endocannabinoid hydrolysis, then decreasing anandamide levels and elevating arachidonic acid levels, and contributing to the destructive inflammatory process that accompanies AD [99,101], despite studies in PS1/APP + mice describing an increase in brain levels of monoacylglycerols, Nacylethanolamines, free fatty acids, eicosanoids, and other lipid species [96].…”