Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50×100μm) and minimal damage to the surrounding parenchyma (50-100μm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α-Bungarotoxin, the potent α7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ42 - induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α7nAChR and varies across hippocampal subfields.
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Oligomeric Aβ interacts with glutamate receptors, contributing to glutamate excitotoxicity.
“Moreover, oligomeric Aβ has been shown to interact with glutamate receptors contributing to glutamate excitotoxicity (Hascup and Hascup 2016).”
From Alzheimer’s disease: Targeting the glutamatergic system (2020) · cites this paper as Hascup and Hascup 2016
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- Authors
- Hascup, K. N., & Hascup, E. R.
- Affiliations
- SIU Medicine (US)
- Corresponding author
- Hascup, Erin R.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2016-06-22
- Volume
- 53
- Issue
- 1
- Pages
- 337-347
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2346422100
- Cited by
- 57
- References
- 51
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 5 · 2020: 10 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 1
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- OpenSIUC (Southern Illinois University Carbondale) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- alpha7 nicotinic acetylcholine receptor
- MeSH terms
- Analysis of Variance, Animals, Bungarotoxins, Dose-Response Relationship, Drug, Electric Stimulation, Hippocampus, Male, Mice, Inbred C57BL, Microelectrodes, Peptide Fragments, Tetrodotoxin, Amyloid beta-Peptides, Glutamic Acid, Sodium Channel Blockers, Mice, alpha7 Nicotinic Acetylcholine Receptor
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