title: Amyloid-beta peptide decreases expression and function of glutamate transporters in nervous system cells.
abstract: Glutamate is an essential excitatory neurotransmitter that regulates brain functions, and its activity is tightly regulated by glutamate transporters. Excess glutamate in the synaptic cleft and dysfunction of excitatory amino acid transporters have been shown to be involved in development of Alzheimer's disease, but the precise regulatory mechanism is poorly understood. Using a D-[3H]-aspartic acid uptake assay, we found that Aβ1-42oligomers impaired glutamate uptake in astrocytes and neurons. In astrocytes, this process was accompanied by reduced expression of GLT-1 and GLAST as detected by Western blot and immunocytofluorescence. However, mRNA levels of EAATs detected by qPCR in astrocytes and neurons were not altered, which suggests that this process is post-translational. Co-localization analysis using immunocytofluorescence showed that ubiquitylation of GLT-1 significantly increased. Therefore, we hypothesized that Aβ1-42oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, Aβ1-42oligomers enhanced secretion of IL-1β, TNF-α, and IL-6 into culture supernatant, which may be correlated with an inflammatory response and altered EAATs expression or function in Alzheimer's disease. These findings support the idea that dysregulation of the glutamatergic system may play a significant role in pathogenesis of Alzheimer's disease. Furthermore, enhancing expression or function of EAATs in astrocytes and neurons might be a new therapeutic approach in treatment of Alzheimer's disease.
authors.affiliation: Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Huichun
authors.initials: H
authors.lastname: Tong
authors.affiliation: Teaching Center of Experimental Medicine, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
authors.forename: Xingjun
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510080, China. Electronic address: pingyixujd@163.com.
authors.forename: Pingyi
authors.initials: P
authors.lastname: Xu
authors.affiliation: Medical Experimental Research Center, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510900, China. Electronic address: 1814925716@qq.com.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China; Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: sgq9528@163.com.
authors.forename: Shaogang
authors.initials: S
authors.lastname: Qu
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D051379:Mice; D050496:Vesicular Glutamate Transport Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D050496:Vesicular Glutamate Transport Proteins
keywords: Alzheimer’s disease; Glutamate transporters; Glutamate uptake; Ubiquitylation