RT Journal Article
SR Electronic
T1 Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3326
OP 3338
DO 10.1523/JNEUROSCI.5098-09.2010
VO 30
IS 9
A1 Allaman, Igor
A1 Gavillet, Mathilde
A1 Bélanger, Mireille
A1 Laroche, Thierry
A1 Viertl, David
A1 Lashuel, Hilal A.
A1 Magistretti, Pierre J.
YR 2010
UL http://www.jneurosci.org/content/30/9/3326.abstract
AB Amyloid-β (Aβ) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy 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 Aβ25-35 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. A causal 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 Aβ25-35 fragment were reproduced by Aβ1-42 but not by Aβ1-40. 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.