Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer's Disease

Abstract

Summary Alzheimer’s disease (AD) is the most common cause of dementia among older people. There are no effective medications currently available to prevent and treat AD and halt disease progression. Monoacylglycerol lipase (MAGL) is the primary enzyme metabolizing the endocannabinoid 2-arachidonoylglycerol in the brain. We show here that inactivation of MAGL robustly suppressed production and accumulation of β-amyloid (Aβ) associated with reduced expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a mouse model of AD. MAGL inhibition also prevented neuroinflammation, decreased neurodegeneration, maintained integrity of hippocampal synaptic structure and function, and improved long-term synaptic plasticity, spatial learning and memory in AD animals. While the molecular mechanisms underlying MAGL inhibition-produced beneficial effects remain to be determined, our results suggest that MAGL, which regulates endocannabinoid and prostaglandin signaling, contributes to pathogenesis and neuropathology of AD and thus is a promising therapeutic target for the prevention and treatment of AD.

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

“…JZL184 was prepared and dissolved in a vehicle containing Tween 80 (10%), dimethylsulfoxide (10%) and saline (80%) as described previously. 19 Repetitively Mild Closed Head Injury A mouse model of rmCHI was used as described previously with modification. 5,23,24 Repetitive brain injuries were induced using an electromagnetic controlled stereotaxic impact device (Impact One Stereotaxic Impactor, Leica Biosystem, Buffalo Grove, IL, USA).…”

“…19,20,25 Cortical and hippocampal tissues were extracted and immediately homogenized in RIPA lysis buffer and protease inhibitors, and incubated on ice for 30 minutes, then centrifuged for 10 minutes at 10,000 r.p.m. at 4°C.…”

“…Indeed, 2-AG possesses significant anti-inflammatory and neuroprotective properties in response to proinflammatory, excitotoxic, and mechanic insults. [16][17][18][19][20][21] The anti-inflammatory and neuroprotective behaviors of 2-AG suggest that manipulation of 2-AG signaling may provide novel therapeutic interventions for the prevention or reduction of TBI-induced neuropathology. 22 As 2-AG is a very unstable fatty acid and is rapidly metabolized by the enzymes upon its release, inhibition of 2-AG metabolism by MAGL inactivation will significantly elevate endogenous 2-AG in the brain.…”

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].…”