Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease
Abstract
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.
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Many astrocyte homeostatic functions have been found to be altered or dysfunctional in AD, such as a decrease in glutamate uptake.
“Many of these functions have been found to be altered or dysfunctional in AD, such as a decrease in glutamate uptake (Scott et al., 2011).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Scott et al., 2011
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- Authors
- Scott, H. A., Gebhardt, F. M., Mitrovic, A. D., Vandenberg, R. J., & Dodd, P. R.
- Affiliations
- The University of Queensland (AU)
- The University of Sydney (AU)
- Corresponding author
- Dodd, Peter R.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 32
- Issue
- 3
- Pages
- 553.e1-553.e11
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2079185455
- Cited by
- 202
- References
- 3
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 22 · 2023: 12 · 2022: 25 · 2021: 17 · 2020: 14 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 11 · 2015: 10 · 2014: 7 · 2013: 6 · 2012: 9
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Judith Jane Mason and Harold Stannett Williams Memorial Foundation
- Alzheimer's Association (RG1-96-005)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- Alzheimer's disease, glutamate transporters, GLT-1, alternative splicing, splice variants, glutamate uptake, glutamate excitotoxicity, astrocytes, selective neuronal vulnerability, glutamate receptor antagonists
- MeSH terms
- Alzheimer Disease, Animals, Autopsy, Bacterial Proteins, Cell Line, Transformed, Cerebral Cortex, Exons, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Luminescent Proteins, Membrane Potentials, Oocytes, RNA Splicing, RNA, Messenger, Transfection, Xenopus laevis, Glutamic Acid, Excitatory Amino Acid Transporter 2, Glutamate Plasma Membrane Transport Proteins
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