Glyceraldehyde-induced metabolic defects in cortical astrocytes: implication for Alzheimer's disease pathogenesis and therapy.

A growing body of evidence suggests that reduced metabolic activity in astrocytes may compromise their normal supportive role for neurons and trigger pathophysiological pathways that contribute to the progression of Alzheimer's disease (AD). Due to the complexity of AD pathophysiology, it is crucial to study the disease not only within those contexts traditionally viewed from a neuron-centric perspective. In this study, we settled up a new model of AD by exposing primary rat cortical astrocytes to glyceraldehyde (GA), an inhibitor of glycolytic pathway able to induce a significant hypometabolism and recapitulate several AD pathomechanisms. Accordingly, GA-induced hypometabolism produced (a) astrocytosis, as revealed by the increase in GFAP and Glutamine Synthase (GS) immunosignals, (b) mitochondrial dysfunction, detected as reduced ATP level, mitochondrial ROS hyperproduction and Ca2 + dyshomeostasis at both cytosolic and mitochondrial level (c) inflammation, measured as NF-κB activation, TNFα release, AGEs hyperproduction/RAGE hyperexpression and increase in S100β immunosignal, and, finally (d) autophagy impairment, characterized by the p62 and LC3II protein accumulation. By virtue of glutamate ability to stimulate cell metabolism, we examined the effect of the neurotransmitter supplementation on cell damage and those correlated mechanisms in the proposed AD model. Of interest, metabolic, inflammatory and autophagy defects were mitigated when astrocytes were exposed to glutamate as metabolic boosting substrate. The protective effect of glutamate was counteracted by the pharmacological inhibition of astrocytic glutamate transporters, thus highlighting the relevance of glutamate intracellular action. Collectively, these results highlight the importance of considering astrocyte-targeted therapies as potential strategy in AD.