Regulation of amyloid precursor protein processing by serotonin signaling.

ABSTRACT: Proteolytic processing of the amyloid precursor protein (APP) by the ?- and ?-secretases releases the amyloid-? peptide (A?), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The ?-secretase cleaves APP in the A? peptide sequence to generate soluble APP? (sAPP?). Upregulation of ?-secretase activity through the 5-hydroxytryptamine 4 (5-HT4) receptor has been shown to reduce A? production, amyloid plaque load and to improve cognitive impairment in transgenic mouse models of AD. Consequently, activation of 5-HT4 receptors following agonist stimulation is considered to be a therapeutic strategy for AD treatment; however, the signaling cascade involved in 5-HT4 receptor-stimulated proteolysis of APP remains to be determined. Here we used chemical and siRNA inhibition to identify the proteins which mediate 5-HT4d receptor-stimulated ?-secretase activity in the SH-SY5Y human neuronal cell line. We show that G protein and Src dependent activation of phospholipase C are required for ?-secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved. Further elucidation of the signaling pathway indicates that inositol triphosphate phosphorylation and casein kinase 2 activation is also a prerequisite for ?-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT4 receptor-induced ?-secretase activation.

SUBMITTER: Pimenova AA 

PROVIDER: S-EPMC3897773 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature