The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: The role of Aβ1-42

Christopher M. Lauderback, Janna M. Hackett, Feng F. Huang, Jeffrey N. Keller, Luke I. Szweda, William R. Markesbery, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

401 Scopus citations

Abstract

Glutamate transporters are involved in the maintenance of synaptic glutamate concentrations. Because of its potential neurotoxicity, clearance of glutamate from the synaptic cleft may be critical for neuronal survival. Inhibition of glutamate uptake from the synapse has been implicated in several neurodegenerative disorders. In particular, glutamate uptake is inhibited in Alzheimer's disease (AD); however, the mechanism of decreased transporter activity is unknown. Oxidative damage in brain is implicated in models of neurodegeneration, as well as in AD. Glutamate transporters are inhibited by oxidative damage from reactive oxygen species and lipid peroxidation products such as 4-hydroxy-2-nonenal (HNE). Therefore, we have investigated a possible connection between the oxidative damage and the decreased glutamate uptake known to occur in AD brain. Western blots of immunoprecipitated HNE-immunoreactive proteins from the inferior parietal lobule of AD and control brains suggest that HNE is conjugated to GLT-1 to a greater extent in the AD brain. A similar analysis of beta amyloid (Aβ)-treated synaptosomes shows for the first time that Aβ1-42 also increases HNE conjugation to the glutamate transporter. Together, our data provide a possible link between the oxidative damage and neurodegeneration in AD, and supports the role of excitotoxicity in the pathogenesis of this disorder. Furthermore, our data suggests that Aβ may be a possible causative agent in this cascade.

Original languageEnglish (US)
Pages (from-to)413-416
Number of pages4
JournalJournal of Neurochemistry
Volume78
Issue number2
DOIs
StatePublished - 2001

Keywords

  • 4-Hydroxy-2-nonenal
  • Alzheimer's disease
  • Beta amyloid
  • Excitotoxicity
  • GLT-1
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: The role of Aβ1-42'. Together they form a unique fingerprint.

Cite this