Influence Of Β-Amyloid Assembly On Synaptosomal Structure And 2-Arachidonoylglycerol Metabolism

Abstract

Among the multiple functions of 2-arachidonoylglycerol (2-AG) in the central nervous system, we can highlight its role as neuroprotective molecule. We have previously demonstrated a deregulation in 2-AG hydrolysis in an in vitro model of Alzheimer´s disease (AD), in rat cerebral cortex synaptosomes (Syn). The aim of the present study was to analyze the effect of βA oligomers (mimicking early AD stage) and fibrils (mimicking late AD stage) in Syn, and also to evaluate 2-AG synthesis by diacylglycerol lipase (DAGL) and lysophosphatidate phosphohydrolase (LPAase) in these AD models. Syn were isolated by differential centrifugation, purified in ficoll gradients, and incubated with different βA peptide conformations. LPAase and DAGL activities were assayed using radiolabeled substrates. We observed that βA oligomers disrupted synaptosomal membranes while fibrils not only caused synaptosome aggregation but also showed membrane damage probably exerted by oligomeric like structures. Also, similarly to 2-AG hydrolysis, its synthesis is differentially modulated in early and late AD stages. Whereas oligomers decreased DAGL activity, fibrils increased both LPAase and DAGL activities. Our results show important differences in early and late AD stages in 2-AG metabolism that could be partially responsible for the neurodegeneration observed in this pathology.