title: Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease.
abstract: 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 Aβ pathology. In primary neuron and astrocyte coculture, naturally secreted Aβ species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Aβ-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Aβ and tau pathology.
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Joannee
authors.initials: J
authors.lastname: Zumkehr
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Rodriguez-Ortiz
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Zanett
authors.initials: Z
authors.lastname: Kieu
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Thin
authors.initials: T
authors.lastname: Wai
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Charlesice
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kilian
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA.
authors.forename: Siok Lam
authors.initials: SL
authors.lastname: Lim
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, USA. Electronic address: mkitazawa@ucmerced.edu.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002443:Ceftriaxone / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D027342:Excitatory Amino Acid Transporter 2; D016875:tau Proteins; D018698:Glutamic Acid; D002443:Ceftriaxone
keywords: Alzheimer's disease; Amyloid β; Astrocyte; GLT-1; Tau