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Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion
Open accessAbstract
Alzheimer's disease amyloid consists of amyloid beta-peptides (Abeta) derived from the larger precursor amyloid precursor protein (APP). Non-amyloidogenic APP processing involves regulated cleavage within the Abeta domain followed by secretion of the ectodomain (APPs). APPs secretion can be stimulated by muscarinic acetylcholine receptors coupled to phospholipases and kinases. To determine whether other receptor classes can regulate APP processing, we examined the relation between serotonin receptors and APPs secretion. Serotonin increased APPs release 3-4-fold in 3T3 cells stably overexpressing 5-HT2aR or 5-HT2cR. The increase was dose-dependent and was blocked by serotoninergic antagonists. Phorbol esters also increased APPs secretion, but neither kinase inhibitors nor down-regulation of PKC blocked the serotonin-induced increase in APPs secretion. Thus PKC is not necessary to stimulate APPs secretion. Phospholipase A2 (PLA2) inhibitors blocked the 5-HT2aR-mediated increase in APPs secretion, suggesting a role of PLA2 in coupling 5-HT2aR to APP processing. In contrast, coupling of 5-HT2cR to APPs secretion involved both PKC and PLA2. Serotonin also stimulated the release of the APLP2 ectodomain, suggesting that additional members of the APP multigene family are processed via similar regulated pathways. Inasmuch as generation of APPs precludes the formation of amyloidogenic derivatives, serotonin receptors provide a novel pharmacological target to reduce these derivatives in Alzheimer's disease.
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“Activation of serotonin receptors has been shown to reduce Aβ production in vitro; treatment with serotonin or receptor agonists activates intracellular signaling cascades and increases levels of the α-secretase product sAPP-α (10–12).”
From An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice (2014) · cites this paper as [11]
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“Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD).”
From An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice (2014) · cites this paper as [11]
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“Activation of select 5HT-Rs increases nonamyloidogenic processing of APP in vitro (14–16)”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [14]
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Buxbaum, J. D., Liu, K.-N., Luo, Y., Slack, J. L., Stocking, K. L., Peschon, J. J., Johnson, R. S., Castner, B. J., Cerretti, D. P., & Black, R. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.27765 · Cited by 952
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Metadata
- Authors
- Nitsch, R. M., Deng, M., Growdon, J. H., & Wurtman, R. J.
- Affiliations
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Nitsch, Roger M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-02
- Volume
- 271
- Issue
- 8
- Pages
- 4188-4194
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2099700886
- Cited by
- 219
- References
- 51
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 2 · 2014: 9 · 2013: 5 · 2012: 6
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institute of Mental Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- 5-HT2A receptor, serotonin 5-HT2C receptor, amyloid precursor protein, amyloid-beta, Alzheimer's disease, phospholipase A2, protein kinase C, muscarinic receptors, APLP2, regulated secretion
- MeSH terms
- Alzheimer Disease, Animals, Humans, Kinetics, Norfenfluramine, Phosphatidylinositols, Receptors, Serotonin, Recombinant Proteins, Serotonin, Transfection, Blotting, Western, Gene Expression, Amyloid beta-Peptides, 3T3 Cells, Amyloid beta-Protein Precursor, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Mice
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