Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the AβPPswe/PS1ΔE9 Mouse Model of Alzheimer's Disease

Abstract

Alterations in the endocannabinoid system (ECS) are thought to play a role in learning and memory impairments observed in Alzheimer's disease (AD). We aimed to determine the status of the brain ECS in the AβPPswe/PS1ΔE9 model of AD. The ECS comprises the neuromodulatory lipid endocannabinoids, anandamide and 2-arachidonoyl glycerol (2AG), which interact with the G protein-coupled type-1 and type-2 cannabinoid receptors. Using mass spectrometry, we quantified endocannabinoid levels and assessed lipidomic profiles of the frontal cortex, hippocampus, and striatum of 4-8 month old wildtype and AβPPswe/PS1ΔE9 mice to determine whether regional variations in endocannabinoids and lipid metabolism are observed with age and disease progression. Additionally, open-field activity, performance in the contextual fear conditioning task, and various other tasks assessing spatial and recognition memory were examined to determine the influence of age and pathology on these parameters. At all ages, AβPPswe/PS1ΔE9 mice were significantly hyperactive in the open-field and acquired contextual fear as well as wildtype mice, reflecting intact associative learning. They, however, exhibited enhanced contextual fear memory and reduced contextual fear extinction regardless of age. Disturbances in striatal lipid metabolism were observed in 6 and 8 month old AβPPswe/PS1ΔE9 mice. Endocannabinoids increased significantly with age in the hippocampus and frontal cortex of both genotypes. 8 month old AβPPswe/PS1ΔE9 mice displayed significantly lower levels of striatal 2AG than wildtype mice, but greater cannabinoid receptor/effector coupling. This study shows that alterations in lipid metabolism and endocannabinoid signaling develop with age in AβPPswe/PS1ΔE9 mice, possibly contributing to the development of AD-like behavioral deficits.

Endocannabinoid system in neurodegenerative disorders

“…ECs were shown to decrease significantly with age in the mouse hippocampus and frontal cortex (Maroof et al . ). An autoradiographic examination of sections of normal post‐mortem brain suggested a no significant reduction in CB1R binding with age (Ahmad et al .…”

“…Eight‐month‐old AβPPswe/PS1ΔE9 mice displayed significantly lower levels of striatal 2‐AG than wild‐type mice but exhibited enhanced cannabinoid receptor/effector coupling (Maroof et al . ). Superfusion of mouse hippocampi with Aβ was reported to significantly prolong depolarization‐induced suppression of inhibition leading to synapse silencing in AD (Mulder et al .…”

“…Limited numbers of studies have reported reduced densities of CB1Rs in aged animals (Mailleux and Vanderhaeghen 1992a;Romero et al 1998). ECs were shown to decrease significantly with age in the mouse hippocampus and frontal cortex (Maroof et al 2014). An autoradiographic examination of sections of normal post-mortem brain suggested a no significant reduction in CB1R binding with age (Ahmad et al 2014).…”

Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice

“…A chimeric mouse/human APP695 with mutations linked to familial AD (APPSwe) was expressed as well as a mutation in the human PS1 gene carrying the exon-9-deleted variant associated with AD (33,34). All experimental animals used in the present work were bred in the University of Nottingham's transgenic animal facility and have been described previously (35,36). Prior to activity monitoring studies, all mice were housed in the same room, maintained on a light/dark (LD) light cycle, with lights on at 07:00 hrs.…”

[18F]FMPEP-d2 PET imaging shows age- and genotype-dependent impairments in the availability of cannabinoid receptor 1 in a mouse model of Alzheimer's disease

“…APP SWE /PS1 DE9 mice have decreased, increased or unchanged CB 1 R availability depending on the age and sex of the animals, as well as the used methods (Kalifa et al, 2011;Karkkainen et al, 2012;Mulder et al, 2011). A more recent study in the same animal model reported increased cannabinoid receptor coupling in the FC and STR, but not in the HIPPO, when TG mice were compared with WT mice (Maroof et al, 2014), whereas an agedependent reduction in CB 1 R levels were reported in the neocortex of APP SWE /PS1 DE9 mice from 6 months of age (Aso et al, 2012). In a 3 Â Tg-AD mouse model, significantly higher CB 1 R mRNA expression was observed in the prefrontal cortex and dorsal HIPPO of 6-and 12-month-old male TG mice and decreased CB 1 R levels in the dorsal HIPPO of 12-month-old TG mice (Bedse et al, 2014).…”