期刊
NEUROBIOLOGY OF AGING
卷 36, 期 7, 页码 2260-2271出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2015.04.005
关键词
Alzheimer's disease; Astrocyte; GLT-1; Tau; Amyloid beta
资金
- Alzheimer's Association Grant [NIRG-12-242598]
Glial glutamate transporter, GLT-1, is the major Na+-driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood. Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Ab pathology. In primary neuron and astrocyte coculture, naturally secreted A beta species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and A beta-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Ab and tau pathology. (C) 2015 Elsevier Inc. All rights reserved.
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