β-Amyloid activates reactive astrocytes by enhancing glycolysis of astrocytes.

Abstract

The aberrant accumulation of β-amyloid peptides (Aβ), reactive astrocytes and glucose metabolism deficit are typical features in the early Alzheimer's disease (AD) pathology. Previous studies have demonstrated that astrocytes process glucose mainly by glycolysis to generate lactate. However, the changes of glycolytic metabolism of reactive astrocytes in AD are still unknown. The present study aims to explore the effect of Aβ on the astrocytic activation and glycolytic metabolism, as well as the role of glycolysis in the activation of astrocytes. The primary astrocytes were cultured and treated with Aβ oligomers, Aβ-activated microglia conditioned medium (aMCM) or the glycogen phosphorylase inhibitor (DAB) for 12h. Then ECAR was used to detect the glycolysis function of reactive astrocytes. The phenotypes of reactive astrocytes were evaluated by detecting the mRNA expression of Gfap (pan-reactive marker), and Ugt1a, Ggta1 (A1-phenotypes markers), and S100a10, Emp1 (A2-phenotypes markers) using qRT-PCR. The levels of GFAP, the marker protein of pan-reactive astrocytes, was also quantified by immunofluorescence and western-blot in Aβ, aMCM or DAB-treated astrocytes. In this study, we found that Aβ oligomers could not directly activate astrocytes or promote the glycolysis. However, Aβ oligomers could induce the activation of neurotoxic A1 astrocytes and up-regulate the glycolysis function via aMCM. Reactivity of A1-astrocytes were inhibited when the glycolytic metabolism was blocked by DAB. The results revealed that Aβ could indirectly activate A1 astrocytes by Aβ-activated microglia, which depended on the up-regulation of the glycolysis of astrocytes. The glycolysis was crucial for the activation of the neurotoxic A1 astrocytes and inhibiting the glycolysis of neurotoxic A1 astrocytes might be a new therapeutic strategy for AD.