Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the A?PPswe/PS1?E9 Mouse Model of Alzheimer's Disease

Maroof, Nazia; Ravipati, Srinivasarao; Pardon, Marie Christine; Barrett, David A.; Kendall, David A.

Abstract

© 2014 - IOS Press and the authors. All rights reserved. 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.

Citation

Maroof, N., Ravipati, S., Pardon, M. C., Barrett, D. A., & Kendall, D. A. (2014). Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the A?PPswe/PS1?E9 Mouse Model of Alzheimer's Disease. Journal of Alzheimer's Disease, 42(1), 227-245. https://doi.org/10.3233/jad-131961

• Journal Article Type: Article
• Acceptance Date: Mar 24, 2014
• Online Publication Date: Aug 11, 2014
• Publication Date: Jan 1, 2014
• Deposit Date: Feb 9, 2017
• Journal: Journal of Alzheimer's Disease
• Electronic ISSN: 1875-8908
• Publisher: IOS Press
• Peer Reviewed: Peer Reviewed
• Volume: 42
• Issue: 1
• Pages: 227-245
• DOI: https://doi.org/10.3233/jad-131961
• Keywords: A?PPswe/PS1?E9, Alzheimer's disease, contextual fear conditioning, endocannabinoids, learning and memory, lipidomics
• Public URL: https://nottingham-repository.worktribe.com/output/1098338
• Publisher URL: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad131961
• PMID: 24844690