Altered Expression of the CB1 Cannabinoid Receptor in the Triple Transgenic Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Bedse, Gaurav^{a; 1} | Romano, Adele^{a; 1} | Cianci, Silvia^a | Lavecchia, Angelo M.^a | Lorenzo, Pace^f | Elphick, Maurice R.^b | LaFerla, Frank M.^c | Vendemiale, Gianluigi^d | Grillo, Caterina^e | Altieri, Fabio^e | Cassano, Tommaso^{f; *} | Gaetani, Silvana^a

Affiliations: [a] Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy | [b] School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London, UK | [c] Department of Neurobiology and Behaviour, University of California, Irvine, CA, USA | [d] Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy | [e] Department of Biochemical Sciences, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy | [f] Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy

Correspondence: [*] Correspondence to: Tommaso Cassano, Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto 1, Foggia 71100, Italy. Tel.: +39 0881 588042; Fax: +39 0881 188 0432; E-mail: tommaso.cassano@unifg.it.

Note: [1] These authors contributed equally to this manuscript.

Abstract: The endocannabinoid system has gained much attention as a new potential pharmacotherapeutic target in various neurodegenerative diseases, including Alzheimer's disease (AD). However, the association between CB1 alterations and the development of AD neuropathology is unclear and often contradictory. In this study, brain CB1 mRNA and CB1 protein levels were analyzed in 3 × Tg-AD mice and compared to wild-type littermates at 2, 6 and 12 months of age, using in-situ hybridization and immunohistochemistry, respectively. Semiquantitative analysis of CB1 expression focused on the prefrontal cortex (PFC), prelimbic cortex, dorsal hippocampus (DH), basolateral amygdala complex (BLA), and ventral hippocampus (VH), all areas with high CB1 densities that are strongly affected by neuropathology in 3 × Tg-AD mice. At 2 months of age, there was no change in CB1 mRNA and protein levels in 3 × Tg-AD mice compared to Non-Tg mice in all brain areas analyzed. However, at 6 and 12 months of age, CB1 mRNA levels were significantly higher in PFC, DH, and BLA, and lower in VH in 3 × Tg-AD mice compared to wild-type littermates. CB1 immunohistochemistry revealed that CB1 protein expression was unchanged in 3 × Tg-AD at 2 and 6 months of age, while a significant decrease in CB1 receptor immunoreactivity was detected in the BLA and DH of 12-month-old 3 × Tg-AD mice, with no sign of alteration in other brain areas. The altered CB1 levels appear, rather, to be age-and/or pathology-dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD.

Keywords: 3 × Tg-AD mice, Alzheimer's disease, basolateral amygdala complex, CB1 mRNA, CB1 receptor, endocannabinoid system, hippocampus, prefrontal cortex

DOI: 10.3233/JAD-131910

Journal: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 701-712, 2014