Cited by 476Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease

Masliah, E., Hansen, L., Alford, M., Deteresa, R., Mallory, M.·1996·Annals of Neurology

Abstract

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

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Crossref · 10.1002/ana.410400512

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73 of 73 references verified0 citation errors · 0 not checkable

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  • Glutamine is produced from glutamate by the activity of glutamine synthetase (GS).

    “Glutamine is produced from glutamate by the activity of glutamine synthetase (GS) [124,131].”
  • GLT-1 activity is decreased in AD brain, likely due to oxidative modification by HNE.

    “but its activity is decreased in AD brain, which is likely due to oxidative modification by HNE [26,131].”
  • The glial glutamate transporter GLT-1 (EAAT2) is responsible for the uptake of synaptic glutamate.

    “The glial glutamate transporter (GLT-1), also known as the excitatory amino acid transporter-2 (EAAT2), is responsible for the uptake of synaptic glutamate”
  • Loss or dysfunction of SLC1A2 has been implicated in multiple neurodegenerative and neuropsychiatric disorders, including AD where it is closely associated with cognitive decline.

    “Loss or dysfunction of SLC1A2 has been implicated in multiple neurodegenerative and neuropsychiatric disorders, including AD where it is closely associated with cognitive decline [126–131].”
  • 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.”

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Authors
Masliah, E., Hansen, L., Alford, M., Deteresa, R., & Mallory, M.
Affiliations
University of California San Diego (US)
Corresponding author
Masliah, E.
Venue
Annals of Neurology
Publisher
Wiley
Published
1996-11
Volume
40
Issue
5
Pages
759-766
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
OpenAlex
W2050523782
Cited by
476
References
73
Citations by year
2026: 13 · 2025: 17 · 2024: 20 · 2023: 17 · 2022: 27 · 2021: 21 · 2020: 24 · 2019: 32 · 2018: 24 · 2017: 17 · 2016: 11 · 2015: 20 · 2014: 13 · 2013: 10 · 2012: 12
FWCI
6.74
Type
journal article
Language
en
Open access
closed
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (AG10689, AG05131, R01AG010689, P50AG005131)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, glutamate transporters, excitotoxicity, neurodegeneration, synapse damage, synaptophysin, synaptic pathology
MeSH terms
Aged, Aspartic Acid, Autopsy, Biological Transport, Brain, Frontal Lobe, Humans, Nerve Degeneration, Organ Specificity, Reference Values, Regression Analysis, Spectrin, Biomarkers, Synaptophysin, Neurofibrillary Tangles, ATP-Binding Cassette Transporters, Amino Acid Transport System X-AG

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