Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

Abstract

BackgroundAlzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.MethodsWe have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET).ResultsNovel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.ConclusionsIn summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer’s Disease

“…The flourish of recent reports of the role of the CB 2 receptor in AD (11) and of the CB 2 receptor manipulation in mouse models of AD (13)(14)(15) suggest that the field of AD therapeutics is moving toward experimental cannabinoid interventions in humans, perhaps targeting the CB 2 receptor. Of note, each of these studies focused on amyloid models of disease, and only one study included tau outcomes (14).…”

“…It was demonstrated that cannabinoid treatment with Aβ prevented microglial activation and that although Aβ-treated mice manifested very typical AD model impairments of spatial navigation, the cannabinoid prevented this Aβ-induced cognitive impairment. Recently, investigators exposed 11-month-old transgene amyloid precusor protein (TgAPP) 2576 mice to prolonged treatment with a synthetic CB 2 receptor agonist, JWH-133 (13). When compared with vehicletreated mice, JWH-133 treatment reduced microgliosis, decreased soluble Aβ40 and Aβ42 and enhanced glucose metabolism in the hippocampus and cortical regions, suggesting that targeting the microglial CB 2 receptor interrupts critical events in the amyloid cascade via a direct impact on microglial activation.…”

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

“…Beneficial effects in preclinical studies involved CB 1 R and/or CB 2 R, the selective activation of which was found to be effective in improving cognitive impairment, preserving neuronal cells, and preventing Aβ-induced microglial activation and the generation of proinflammatory mediators, as well as removing pathological deposits in different in vivo and in vitro models of AD [86][87][88][89][90]. 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].…”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

“…The endocannabinoid system is a complex network of cellular receptors and signaling molecules [7] highly expressed in brain and targeted by cannabis derivatives which, when activated, provides neuroprotection by reducing neuronal damage, neuroinflammation, and oxidative stress, as well as promoting intrinsic repair mechanisms [3]. Thus, chronic stimulation with selective synthetic agonists of CB 1 and CB 2 receptors, the most well-known cannabinoid receptors, reduces cognitive impairment and brain alterations associated with A␤ production, in at least three different animal models of AD [8][9][10][11]. Moreover, the combination of 9 -tetrahydrocannabinol ( 9 -THC) and cannabidiol (CBD), two phytocannabinoids produced by the plant Cannabis sativa, reduces the pathological phenotype in mouse models of AD and tauopathy when administered at early stages of the disease [12,13].…”