Yuhan Zhang1,2, Xiu Yang1,2, Jingchao Zhuang1,2, Hongquan Zhang1,2, Can Gao3,4. 1. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, 221004, Xuzhou, Jiangsu, China. 2. Xuzhou Medical University, 209 Tongshan Road, 221004, Xuzhou, Jiangsu, China. 3. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application, Xuzhou Medical University, 221004, Xuzhou, Jiangsu, China. gaocan@xzhmu.edu.cn. 4. Xuzhou Medical University, 209 Tongshan Road, 221004, Xuzhou, Jiangsu, China. gaocan@xzhmu.edu.cn.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: The primary astrocytes were cultured and treated with Aβ oligomers, Aβ-activated microglia conditioned medium (aMCM) or the glycogen phosphorylase inhibitor (DAB) for 12 h. 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS AND RESULTS: The primary astrocytes were cultured and treated with Aβ oligomers, Aβ-activated microglia conditioned medium (aMCM) or the glycogen phosphorylase inhibitor (DAB) for 12 h. 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. CONCLUSIONS: 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.
Authors: Stephen F Carter; Karl Herholz; Pedro Rosa-Neto; Luc Pellerin; Agneta Nordberg; Eduardo R Zimmer Journal: Trends Mol Med Date: 2019-01-02 Impact factor: 11.951
Authors: Erik C B Johnson; Eric B Dammer; Duc M Duong; Lingyan Ping; Maotian Zhou; Luming Yin; Lenora A Higginbotham; Andrew Guajardo; Bartholomew White; Juan C Troncoso; Madhav Thambisetty; Thomas J Montine; Edward B Lee; John Q Trojanowski; Thomas G Beach; Eric M Reiman; Vahram Haroutunian; Minghui Wang; Eric Schadt; Bin Zhang; Dennis W Dickson; Nilüfer Ertekin-Taner; Todd E Golde; Vladislav A Petyuk; Philip L De Jager; David A Bennett; Thomas S Wingo; Srikant Rangaraju; Ihab Hajjar; Joshua M Shulman; James J Lah; Allan I Levey; Nicholas T Seyfried Journal: Nat Med Date: 2020-04-13 Impact factor: 53.440
Authors: Veit Rothhammer; Davis M Borucki; Emily C Tjon; Maisa C Takenaka; Chun-Cheih Chao; Alberto Ardura-Fabregat; Kalil Alves de Lima; Cristina Gutiérrez-Vázquez; Patrick Hewson; Ori Staszewski; Manon Blain; Luke Healy; Tradite Neziraj; Matilde Borio; Michael Wheeler; Loic Lionel Dragin; David A Laplaud; Jack Antel; Jorge Ivan Alvarez; Marco Prinz; Francisco J Quintana Journal: Nature Date: 2018-05-16 Impact factor: 49.962
Authors: Rui Hu; Pan Wei; Lu Jin; Teng Zheng; Wen-Yu Chen; Xiao-Ya Liu; Xiao-Dong Shi; Jing-Ru Hao; Nan Sun; Can Gao Journal: Cell Death Dis Date: 2017-03-30 Impact factor: 8.469