Normal ageing in rats and pathological ageing in human Alzheimer's disease decrease FAAH activity: Modulation by cannabinoid agonists

PASCUAL, A.C.; MARTÍN-MORENO, A. M.; GIUSTO, N.M.; DE CEBALLOS, M. L.; PASQUARÉ, S.J.

EXPERIMENTAL GERONTOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2014 vol. 60 p. 92 - 99

0531-5565

Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological ageing and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analysed in an independent cohort of human cortical membrane samples from control and Alzheimer´s disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in frontal cortex from human patients with Alzheimer´s disease and this effect is mimicked by amyliod beta 1-40 peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN 55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer´s disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer´s disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer´s disease and to an increased availability of this endocannabinoid in ageing.