| First Author | Ye B | Year | 2015 |
| Journal | Glia | Volume | 63 |
| Issue | 12 | Pages | 2208-19 |
| PubMed ID | 26200696 | Mgi Jnum | J:279975 |
| Mgi Id | MGI:6368305 | Doi | 10.1002/glia.22886 |
| Citation | Ye B, et al. (2015) Dual pathways mediate beta-amyloid stimulated glutathione release from astrocytes. Glia 63(12):2208-19 |
| abstractText | 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 (Abeta42), crucially involved in Alzheimer's disease, affected GSH release. Monomeric Abeta (mAbeta) stimulated GSH release from cultured cortical astrocytes more effectively than oligomeric Abeta (oAbeta) or fibrillary Abeta (fAbeta). Monomeric Abeta 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 mAbeta stimulation, was reduced by pharmacological inhibition of ABCC1. Astrocytes robustly express connexin proteins, especially connexin43 (Cx43), and mAbeta also stimulated Cx43 hemichannel-mediated glutamate and GSH release. Abeta-stimulation facilitated hemichannel opening in the presence of normal extracellular calcium by reducing astrocyte cholesterol level. Abeta treatment did not alter the intracellular concentration of reduced or oxidized glutathione. Using a mouse model of AD with early onset Abeta deposition (5xFAD), we found that cortical ABCC1 was significantly increased in temporal register with the surge of Abeta 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 Abeta, but not mAbeta, reduced induction of ABCC1 expression. These results support the hypothesis that in the early stage of AD pathogenesis, less aggregated Abeta increases GSH release from astrocytes (via ABCC1 transporters and Cx43 hemichannels) providing temporary protection from oxidative stress which promotes AD development. |
