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Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures.
Proc Natl Acad Sci U S A. 2019 10 22; 116(43):21800-21811.PN

Abstract

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.

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Authors+Show Affiliations

Sharma A
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Kazim SF
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Larson CS
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
Ramakrishnan A
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Gray JD
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
McEwen BS
Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@mail.rockefeller.edu ana.pereira@mssm.edu.
Rosenberg PA
Department of Neurology and the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115. Program in Neuroscience, Harvard Medical School, Boston, MA 02115.
Shen L
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Pereira AC
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; mcewen@mail.rockefeller.edu ana.pereira@mssm.edu. Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

MeSH

AdultAged, 80 and overAgingAlzheimer DiseaseAnimalsAstrocytesCognitionCognitive DysfunctionExcitatory Amino Acid Transporter 2HippocampusHumansKynurenineMaleMemory DisordersMemory, Long-TermMemory, Short-TermMiceMice, KnockoutMiddle AgedNeuronsYoung Adult

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31591195

Citation

Sharma, Abhijeet, et al. "Divergent Roles of Astrocytic Versus Neuronal EAAT2 Deficiency On Cognition and Overlap With Aging and Alzheimer's Molecular Signatures." Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 43, 2019, pp. 21800-21811.
Sharma A, Kazim SF, Larson CS, et al. Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures. Proc Natl Acad Sci U S A. 2019;116(43):21800-21811.
Sharma, A., Kazim, S. F., Larson, C. S., Ramakrishnan, A., Gray, J. D., McEwen, B. S., Rosenberg, P. A., Shen, L., & Pereira, A. C. (2019). Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures. Proceedings of the National Academy of Sciences of the United States of America, 116(43), 21800-21811. https://doi.org/10.1073/pnas.1903566116
Sharma A, et al. Divergent Roles of Astrocytic Versus Neuronal EAAT2 Deficiency On Cognition and Overlap With Aging and Alzheimer's Molecular Signatures. Proc Natl Acad Sci U S A. 2019 10 22;116(43):21800-21811. PubMed PMID: 31591195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer's molecular signatures. AU - Sharma,Abhijeet, AU - Kazim,Syed Faraz, AU - Larson,Chloe S, AU - Ramakrishnan,Aarthi, AU - Gray,Jason D, AU - McEwen,Bruce S, AU - Rosenberg,Paul A, AU - Shen,Li, AU - Pereira,Ana C, Y1 - 2019/10/07/ PY - 2019/10/9/pubmed PY - 2020/4/9/medline PY - 2019/10/9/entrez KW - Alzheimer’s disease KW - aging KW - glutamate transporter SP - 21800 EP - 21811 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 116 IS - 43 N2 - The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer's disease (AD) patients' brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/31591195/Divergent_roles_of_astrocytic_versus_neuronal_EAAT2_deficiency_on_cognition_and_overlap_with_aging_and_Alzheimer's_molecular_signatures_ DB - PRIME DP - Unbound Medicine ER -
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