Synaptic NMDA Receptor Activation Stimulates α-Secretase Amyloid Precursor Protein Processing and Inhibits Amyloid-β Production
Open accessAbstract
Altered amyloid precursor protein (APP) processing leading to increased production and oligomerization of Aβ may contribute to Alzheimer's disease (AD). Understanding how APP processing is regulated under physiological conditions may provide new insights into AD pathogenesis. Recent reports demonstrate that excitatory neural activity regulates APP metabolism and Aβ levels, although understanding of the molecular mechanisms involved is incomplete. We have investigated whether NMDA receptor activity regulates APP metabolism in primary cultured cortical neurons. We report that a pool of APP is localized to the postsynaptic compartment in cortical neurons and observed partial overlap of APP with both NR1 and PSD-95. NMDA receptor stimulation increased nonamyloidogenic α-secretase-mediated APP processing, as measured by a 2.5-fold increase in cellular α-C-terminal fragment (C83) levels after glutamate or NMDA treatment. This increase was blocked by the NMDA receptor antagonists d -AP5 and MK801 but not by the AMPA receptor antagonist CNQX or the L-type calcium channel blocker nifedipine, was prevented by chelation of extracellular calcium, and was blocked by the α-secretase inhibitor TAPI-1. Cotreatment of cortical neurons with bicuculline and 4-AP, which stimulates glutamate release and activates synaptic NMDA receptors, evoked an MK801-sensitive increase in C83 levels. Furthermore, NMDA receptor stimulation caused a twofold increase in the amount of soluble APP detected in the neuronal culture medium. Finally, NMDA receptor activity inhibited both Aβ1-40 release and Gal4-dependent luciferase activity induced by β-γ-secretase-mediated cleavage of an APP-Gal4 fusion protein. Altogether, these data suggest that calcium influx through synaptic NMDA receptors promotes nonamyloidogenic α-secretase-mediated APP processing.
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Glutamate NMDA receptors activate intracellular signaling cascades that suppress Aβ production.
“For example, glutamate NMDA receptors activate intracellular signaling cascades that suppress Aβ production (7).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [7]
The section on NMDA receptor activity and Aβ release reports that NMDA stimulation decreases Aβ1-40 release. The mechanism-of-action section proposes increased α-secretase cleavage of APP as an explanation, while the section on glutamate-induced C83 levels links receptor activation to calcium-dependent cellular signaling. The paper does not establish that specific intracellular signaling cascades mediate the suppression of Aβ production. (LLM, conf=0.80)
Experimental — accuracy not yet measuredSynaptic activity regulates Aβ levels through neurotransmitter-activated second messenger signaling pathways that alter APP processing into Aβ.
“Synaptic activity is known to regulate Aβ levels through a presynaptic mechanism that is dependent on APP endocytosis and cleavage (4, 5) and through neurotransmitter-activated second messenger signaling pathways that alter APP processing into Aβ (7, 11, 12, 31).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [7]
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- Authors
- Hoey, S. E., Williams, R. J., & Perkinton, M. S.
- Affiliations
- King's College London (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-04-08
- Volume
- 29
- Issue
- 14
- Pages
- 4442-4460
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665739
- OpenAlex
- W1983247143
- Cited by
- 178
- References
- 11
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 16 · 2018: 12 · 2017: 15 · 2016: 7 · 2015: 10 · 2014: 15 · 2013: 15 · 2012: 14
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Alzheimer's Society
- 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
- NMDA receptor, APP processing, alpha-secretase, amyloid-beta production, Alzheimer's disease, cortical neurons, NR1, PSD-95, glutamate release, soluble APP
- MeSH terms
- Animals, Cells, Cultured, Humans, Peptide Fragments, Protein Processing, Post-Translational, Synapses, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Mice, Amyloid Precursor Protein Secretases
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