Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA Receptors In Vivo
Open accessAbstract
The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer's disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo . This has implications for understanding normal Aβ metabolism as well as AD pathogenesis.
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Synaptic 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 [31]
The NMDA-induced reduction in ISF Aβ was blocked by ERK and MEK inhibitors.
“In contrast, infusion of NMDA, which can also activate ERK (29), significantly lowered ISF Aβ levels by over 50% (Fig. S3); this reduction was blocked by ERK and MEK inhibitors (31).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [31]
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Cites
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- Authors
- Verges, D. K., Restivo, J. L., Goebel, W. D., Holtzman, D. M., & Cirrito, J. R.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-08-03
- Volume
- 31
- Issue
- 31
- Pages
- 11328-11337
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3329800
- OpenAlex
- W2001580754
- Cited by
- 74
- References
- 8
- Citations by year
- 2026: 3 · 2025: 6 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 10 · 2013: 9 · 2012: 6
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institute on Aging (P50 AG568127, K01AG029524, AG029524)
- 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
- amyloid-beta metabolism, NMDA receptor, synaptic activity, brain interstitial fluid, Alzheimer's disease, APP processing, ERK signaling, synaptic transmission, NMDA receptor antagonists
- MeSH terms
- Action Potentials, Analysis of Variance, Animals, Calcium, Chelating Agents, Dose-Response Relationship, Drug, Egtazic Acid, Electroencephalography, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Extracellular Space, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Piperazines, Piperidines, Pregnanolone, Serotonin, Synapses, Tetrodotoxin, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Excitatory Amino Acid Antagonists, Sodium Channel Blockers, Flavones, Extracellular Signal-Regulated MAP Kinases, Mice, Presenilin-1, Brain Waves
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