Dual Pathways Mediate β-Amyloid Stimulated Glutathione Release from Astrocytes

Oxidative stress plays an important role in the progression of Alzheimer's disease (AD) and other neurodegenerative conditions. Glutathione (GSH), the major antioxidant in the central nervous system, is primarily synthesized and released by astrocytes. We determined if beta-amyloid (A beta 42), crucially involved in Alzheimer's disease, affected GSH release. Monomeric A beta (mAb) stimulated GSH release from cultured cortical astrocytes more effectively than oligomeric A beta (oA beta) or fibrillary A beta (fAb). Monomeric A beta increased the expression of the transporter ABCC1 (also referred to as MRP1) that is the main pathway for GSH release. GSH release from astrocytes, with or without mA beta stimulation, was reduced by pharmacological inhibition of ABCC1. Astrocytes robustly express connexin proteins, especially connexin43 (Cx43), and mA beta also stimulated Cx43 hemichannel-mediated glutamate and GSH release. A beta-stimulation facilitated hemichannel opening in the presence of normal extracellular calcium by reducing astrocyte cholesterol level. A beta treatment did not alter the intracellular concentration of reduced or oxidized glutathione. Using a mouse model of AD with early onset A beta deposition (5xFAD), we found that cortical ABCC1 was significantly increased in temporal register with the surge of A beta levels in these mice. ABCC1 levels remained elevated from 1.5 to 3.5 months of age in 5xFAD mice, before plunging to subcontrol levels when amyloid plaques appeared. Similarly, in cultured astrocytes, prolonged incubation with aggregated A beta, but not mA beta, reduced induction of ABCC1 expression. These results support the hypothesis that in the early stage of AD pathogenesis, less aggregated A beta increases GSH release from astrocytes (via ABCC1 transporters and Cx43 hemichannels) providing temporary protection from oxidative stress which promotes AD development.