title: 5-HT4 receptors constitutively promote the non-amyloidogenic pathway of APP cleavage and interact with ADAM10.
abstract: In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT(4)Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT(4) receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT(4) receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing.
authors: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.
authors: Maud
authors: M
authors: Cochet
authors: Romain
authors: R
authors: Donneger
authors: Elisabeth
authors: E
authors: Cassier
authors: Florence
authors: F
authors: Gaven
authors: Stefan F
authors: SF
authors: Lichtenthaler
authors: Philippe
authors: P
authors: Marin
authors: Joël
authors: J
authors: Bockaert
authors: Aline
authors: A
authors: Dumuis
authors: Sylvie
authors: S
authors: Claeysen
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000209:etiology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001572:Benzofurans / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism / Q000502:physiology*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D058828:Serotonin 5-HT4 Receptor Agonists; C406662:prucalopride; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human