Expresión y Funcionalidad de Receptores de Cannabinoides y de Adenosina y de sus Heterómeros en modelos de Alzheimer y de Esclerosis Múltiple

Abstract

[eng] Adenosine and endocannabinoids are regulatory molecules that are present in all organ and physiological systems. They act via specific receptors belonging to the G protein-coupled receptor (GPCR) superfamily. There are four adenosine receptors, A1, A2A, A2B and A3, that, in the central nervous system, are expressed in both neurons and glia. There are two cannabinoid receptors, CB1 that is much more expressed in neurons than in glia, and CB2 that is mainly expressed in glia. GPCR may form receptor-receptor complexes, both homo and heteromers, with specific properties. The aim of this PhD was to get insight into the potential of cannabinoid, of adenosine receptors and of their heteromers to become targets of Alzheimer’s disease and of multiple sclerosis. Both expression and functionality of some receptors and of some receptor heteromers were addressed. In addition, a novel technique aimed at assessing the percentage of receptors that are forming heteromers was used to demonstrate, in a heterologous system, a differential effect of adenosine and caffeine on the expression of A1R, A2AR and A1-A2A receptor heteromers on the cell surface. The technique also allowed to show increased heteromer expression in primary cultures of activated astroglial cells (versus resting cells). Astroglia showed expression of the A1-CB1 receptor heteromer whose functionality was characterized by a negative crosstalk and a crossantagonism; crossantagonism due to the A1-CB1 receptor heteromer was also found in primary cortical neurons. Finally, the heteromer formed by CB1R and the N-methyl-D-aspartate ionotropic glutamate receptor (NMDAR) was identified and characterized in both heterologous systems and primary neurons. The results showed that CB1R activation blocks NMDAR function and crossantagonism is detected. Increased expression of the CB1R-NMDAR heteromer in primary cortical neurons treated with β-amyloid peptide suggests that targeting the heteromer may provide benefits in combating the detrimental effect of amyloid aggregation.