Amyloid-β aggregates cause alterations of astrocytic metabolic phenotype: Impact on neuronal viability

Amyloid-β(Aβ) peptidesplayakeyrole inthepathogenesisofAlzheimer'sdiseaseandexertvarioustoxic effectsonneurons; however,relatively little isknownabouttheir influenceonglial cells. Astrocytes playapivotal role inbrainhomeostasis,contributing to the regulation of localenergy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Aβ peptides on glucose metabolism in cultured astrocytes. Following Aβ_25-35 exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Aβ increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content.Acausal link between the effects of Aβ on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Aβ impair neuronal viability. The effects of the Aβ_25-35 fragment were reproduced by Aβ_1-42 but not by Aβ_1-40. Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Aβ aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.