Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer’s Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine

Article type: Research Article

Authors: Aso, Ester^{a; b; *} | Andrés-Benito, Pol^{a; b} | Carmona, Margarita^{a; b} | Maldonado, Rafael^c | Ferrer, Isidre^{a; b}

Affiliations: [a] Institut de Neuropatologia, Servei d’Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain | [b] CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Spain | [c] Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

Correspondence: [*] Correspondence to: Ester Aso, Institut de Neuropatologia, Servei d’Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, C/Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Spain. Tel.: +34 93 2607452; Fax: +34 93 2607503; E-mail: [email protected].

Abstract: The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer’s disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.

Keywords: AβPP/PS1 mice, Alzheimer’s disease, amyloid, cannabinoid receptor 2, cognitive impairment, Δ⁹-tetrahidrocannabinol and cannabidiol, tau, therapy

DOI: 10.3233/JAD-150913

Journal: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 489-500, 2016