5-HT4 Receptors Constitutively Promote the Non-amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

Overview

Journal ACS Chem Neurosci

Publisher American Chemical Society

Specialty Neurology

Date 2013 Jan 22

PMID 23336052

Citations 36

Authors

Maud Cochet

Romain Donneger

Elisabeth Cassier

Florence Gaven

Stefan F Lichtenthaler

Philippe Marin

Joel Bockaert

Aline Dumuis

Sylvie Claeysen

Affiliations

Soon will be listed here.

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.

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