Endocannabinoid hydrolysis changes in different subcellular fractions from the central nervous system by beta amyliod peptide and polyunsaturated fatty acid

PASCUAL, A.C.; GAVEGLIO, V.L.; GIUSTO, N.M.; PASQUARÉ, S.J.

Puerto Iguazú

Conferencia; 56th International Conference on the Bioscience of Lipids; 2015

International Conference on the Bioscience of Lipids (ICBL)

2-arachidonoylglycerol (2-AG) and anandamide (AEA) are the main endocannabinoids known to date. Among their several functions in the CNS we can highlight their role as neuroprotective agents. In respect to this, endocannabinoids participate in the modulation of numerous cellular and molecular events related to neurodegeneration in physiological and pathological aging. Endocannabinoid system is well characterized in synaptic endings but it has been recently evidenced the existence of an active nuclei metabolism. 2-AG hydrolysis is carried out mainly by monoacylglycerol lipase (MAGL) while fatty acid amide hydrolase (FAAH) is responsible for AEA hydrolysis. We have previously demonstrated the regulation of nuclear 2-AG metabolism by fatty acids in adult rat cerebellum and a deregulation in rat cerebral cortex (CC) endocannabinoid metabolism during aging. The aim of the present study was to characterize: i) the modulation of 2-AG hydrolysis by arachidonic acid (AA) and docosahexaenoic acid (DHA) in aged cerebellar nuclei, and ii) 2-AG and AEA hydrolysis in an in vitro model of Alzheimer´s Disease (AD) consisting on rat CC synaptosomes preincubated with beta amyloid peptide oligomers (mimicking early AD stages) and fibrills (mimicking late AD satages). In contrast to adult, aged animal 2-AG hydrolysis was not modified by the presence of AA in cerebellar nuclei; however DHA decreased this activity probably increasing 2-AG nuclear availability. The studies in CC synaptosomes showed that 2-AG and AEA hydrolysis in the early AD model diminished, thus indicating that both endocannabinoid levels could be increased and therefore protect the cell against neurodegenerative processes. Moreover, in the late AD model AEA hydrolysis decreased while 2-AG breakdown highly increased, thus compromising the neuroprotective role assigned to 2-AG. Our results therefore demonstrate that endocannabinoid metabolism in CNS is differentially modulated in aging and also in early and late stages of AD.