5-HT4 receptors constitutively promote the non-amyloidogenic pathway of APP cleavage and interact with ADAM10
ACS Chem. Neurosci.. 2012-10-25; 4(1): 130-140
DOI: 10.1021/cn300095t
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Cochet M(1), Donneger R, Cassier E, Gaven F, Lichtenthaler SF, Marin P, BockaertJ, Dumuis A, Claeysen S.
Author information:
(1)CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier,France.
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.