Cited by 220Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

Serotonin 5-HT2a and 5-HT2c Receptors Stimulate Amyloid Precursor Protein Ectodomain Secretion

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Nitsch, Roger M., Deng, Meihua, Growdon, John H., Wurtman, Richard J.·1996·Journal of Biological Chemistry

Abstract

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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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
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Massachusetts General Hospital
  • National Institute of Mental Health
Topics
  • Health Sciences › Medicine › Physiology › 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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