Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease.
A characteristic of Alzheimer's disease (AD) is that neuron populations in the temporal, frontal, and parietal cortices are selectively vulnerable. Several neurotransmitters have been proposed to play roles in neural destruction as AD progresses, including glutamate. Failure to clear the synaptic cleft of glutamate can overstimulate postsynaptic glutamate receptors, promoting neuronal death. Excitatory amino acid transporter 2 (EAAT2), which is concentrated in perisynaptic astrocytes, performs 90% of glutamate uptake in mammalian central nervous system. Alternative splicing of EAAT2 mRNA could regulate glutamate transport in normal and disease states. We report disease- and pathology-specific variations in EAAT2 splice variant expression in AD brain obtained at autopsy. While wild type EAAT2 showed a global reduction in expression, brain regions susceptible to neuronal loss demonstrated greater expression of transcripts that reduced glutamate transport in an in vitro assay. Functional splice variant EAAT2b showed no significant variation with disease state. These results have implications for the treatment of AD as modulators of EAAT2 splicing and/or glutamate uptake would augment current therapies aimed at blocking glutamate receptors.
Scott
Heather A
HA
School of Chemistry and Molecular Biosciences, University of Queensland, Queensland, Australia.
Gebhardt
Florian M
FM
Mitrovic
Ann D
AD
Vandenberg
Robert J
RJ
Dodd
Peter R
PR
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001344:Autopsy / Q000379:methods; D001426:Bacterial Proteins / Q000235:genetics; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009865:Oocytes; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
D001426:Bacterial Proteins; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; D012333:RNA, Messenger; C493397:SLC1A2 protein, human; C054562:yellow fluorescent protein, Bacteria; D018698:Glutamic Acid