Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures
Open accessAbstract
Significance: The excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter in the mammalian brain, and its expression is reduced in aging and sporadic Alzheimer’s disease (AD) brains. The mechanisms through which reduced EAAT2 expression contributes to cognitive decline and AD-related neurodegeneration and the differential functional roles of its astrocytic and neuronal components remain largely unknown. This study uses behavioral analysis to show that astrocytic and neuronal EAAT2 deficiency in mice causes age-dependent cognitive dysfunction. Furthermore, we show that gene expression from human AD and aging datasets have a robust overlap with astrocytic EAAT2 deficiency. This study highlights the distinct signaling mechanisms mediated by neuronal and astrocytic EAAT2 and EAAT2 as a potential therapeutic target in aging and AD.
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EAAT2 expression diminishes with age and correlates with signs of neuronal death in postmortem brains of sporadic AD patients.
“EAAT2 expression diminishes with age60 and correlates with signs of neuronal death in postmortem brains of sporadic AD patients61.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [60]
EAAT2 expression diminishes with age.
“Its expression diminishes with age55”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [55]
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- Authors
- Sharma, A., Kazim, S. F., Larson, C. S., Ramakrishnan, A., Gray, J. D., McEwen, B. S., Rosenberg, P. A., Shen, L., & Pereira, A. C.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Rockefeller University (US)
- Boston Children's Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-10-07
- Volume
- 116
- Issue
- 43
- Pages
- 21800-21811
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6815169
- OpenAlex
- W2979780686
- Cited by
- 92
- References
- 15
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 16 · 2023: 11 · 2022: 17 · 2021: 16 · 2020: 9
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR001866)
- National Institute on Aging (R01AG063819, K76AG054772)
- National Institute of Mental Health (P50MH096890, R21MH104318)
- National Institute of Neurological Disorders and Stroke (R01NS066019)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- GLT-1, astrocytes, neurons, Alzheimer's disease, cognitive aging, memory impairment, hippocampal-dependent memory, kynurenine pathway, neuroinflammation, innate and adaptive immunity, gene expression signatures, glutamate uptake, conditional gene deletion
- MeSH terms
- Adult, Aged, 80 and over, Aging, Alzheimer Disease, Animals, Astrocytes, Cognition, Hippocampus, Humans, Kynurenine, Male, Memory Disorders, Memory, Short-Term, Middle Aged, Neurons, Mice, Knockout, Excitatory Amino Acid Transporter 2, Mice, Young Adult, Memory, Long-Term, Cognitive Dysfunction
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