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

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• 作者：Maud Cochet ; Romain Donneger ; Elisabeth Cassier ; Florence Gaven ; Stefan F. Lichtenthaler ; Philippe Marin ; Jo毛l Bockaert ; Aline Dumuis ; Sylvie Claeysen
• 刊名：ACS Chemical Neuroscience
• 出版年：2013
• 出版时间：January 16, 2013
• 年：2013
• 卷：4
• 期：1
• 页码：130-140
• 全文大小：622K
• 年卷期：v.4,no.1(January 16, 2013)
• ISSN：1948-7193

文摘

In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by 伪-secretases, producing soluble and neuroprotective APP alpha (sAPP伪) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-尾. However, the mechanisms regulating APP cleavage by 伪-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT₄Rs) constitutively (without agonist stimulation) induced APP cleavage by the 伪-secretase ADAM10 and the release of neuroprotective sAPP伪 in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT₄ receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT₄ receptors by an agonist further increased sAPP伪 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 伪-secretase and promotes the nonamyloidogenic pathway of APP processing.

Keywords:

Alpha-secretase; Alzheimer鈥檚 disease; sAPP alpha; serotonin