Common and divergent pathways in early stages of glutamate and tau-mediated toxicities in neurodegeneration
Abstract
It has been shown that excitotoxicity and tau-mediated toxicities are major contributing factors to neuronal death in Alzheimer's disease (AD). The excitatory amino acid transporter 2 (EAAT2 or GLT-1), the major glutamate transporter in the brain that regulates glutamate levels synaptically and extrasynaptically, has been shown to be deficient in AD brains, leading to excitotoxicity and subsequent cell death. Similarly, buildup of neurofibrillary tangles, which consist of hyperphosphorylated tau protein, correlates with cognitive decline and neuronal atrophy in AD. However, common genes and pathways that are critical in the aforementioned toxicities have not been well elucidated. To investigate the impact of glutamate dyshomeostasis and tau accumulation on translational profiles of affected hippocampal neurons, we used mouse models of excitotoxicity and tau-mediated toxicities (GLT-1-/- and P301S, respectively) in conjunction with BAC-TRAP technology. Our data show that GLT-1 deficiency in CA3 pyramidal neurons leads to translational signatures characterized by dysregulation of pathways associated with synaptic plasticity and neuronal survival, while the P301S mutation induces changes in endocytic pathways and mitochondrial dysfunction. Finally, the commonly dysregulated pathways include impaired ion homeostasis and metabolic pathways. These common pathways may shed light on potential therapeutic targets for ameliorating glutamate and tau-mediated toxicities in AD.
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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].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [126]
The Introduction (page unavailable) identifies SLC1A2 as EAAT2/GLT-1, reports its deficiency in AD brains, and says GLT-1 deficiency accelerated cognitive decline in mice. The Discussion (page unavailable) also links reduced GLT-1 to AD and reports improved cognitive markers after GLT-1 overexpression in AD mouse models. These passages support an AD-related connection, but do not establish a close association with cognitive decline in people with AD or implicate SLC1A2 dysfunction in multiple neuropsychiatric disorders. (LLM, conf=0.85)
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- Authors
- Chongtham, A., Sharma, A., Nath, B., Murtha, K., Gorbachev, K., Ramakrishnan, A., Schmidt, E. F., Shen, L., & Pereira, A. C.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Rockefeller University (US)
- Corresponding author
- Pereira, Ana C.
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 382
- Pages
- 114967
- ISSN
- 0014-4886 (ISSN-L)
- PMC
- PMC12670583
- OpenAlex
- W4402759222
- Cited by
- 10
- References
- 95
- Citations by year
- 2026: 6 · 2025: 4
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Robert J and Claire Pasarow Foundation
- National Institutes of Health (R01AG064020, K76 AG054772, R01 AG063819)
- Aspen Center for Physics
- BrightFocus Foundation
- Dana Foundation
- Alzheimer's Association
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, excitotoxicity, GLT-1, neurofibrillary tangles, hippocampal CA3 pyramidal neurons, translational profiling, synaptic plasticity, endocytic pathway, mitochondrial dysfunction, ion homeostasis, metabolic pathways, neuronal survival
- MeSH terms
- Animals, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, Signal Transduction, tau Proteins, Glutamic Acid, Neurodegenerative Diseases, Excitatory Amino Acid Transporter 2, Mice
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