期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 85, 期 -, 页码 75-84出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2017.01.017
关键词
Alzheimer's disease; Glutamate transporters; Glutamate uptake; Ubiquitylation
资金
- National Natural Science Foundation of China [31570716, U1603281]
- Science and Technology Planning Project of Guangdong Province [2012B050200003, 2013B021800305, 2016A050502025]
- Science and Technology Planning Project of Guangzhou [2013J4500018, 2014J4100008]
- Scientific and Technological Innovation Programs of the Higher Education Institution in Guangdong [2013KJCX0041]
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-[H-3]-aspartic acid uptake assay, we found that A beta(1-42) oligomers 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 A beta(1-42) oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, A beta(1-42) oligomers enhanced secretion of IL-beta,TNF-alpha, 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. (C) 2017 Elsevier Ltd. All rights reserved.
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