Regulation of amyloid precursor protein processing by serotonin signaling.
Proteolytic processing of the amyloid precursor protein (APP) by the β- and γ-secretases releases the amyloid-β peptide (Aβ), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The α-secretase cleaves APP in the Aβ peptide sequence to generate soluble APPα (sAPPα). Upregulation of α-secretase activity through the 5-hydroxytryptamine 4 (5-HT4) receptor has been shown to reduce Aβ 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 α-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 α-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 α-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT4 receptor-induced α-secretase activation.
KU Leuven Center for Human Genetics and Leuven research Institute for Neuroscience and Disease (LIND), Leuven, Belgium ; VIB Center for the Biology of Disease, Leuven, Belgium.
Anna A
AA
Pimenova
KU Leuven Center for Human Genetics and Leuven research Institute for Neuroscience and Disease (LIND), Leuven, Belgium ; VIB Center for the Biology of Disease, Leuven, Belgium.
Amantha
A
Thathiah
KU Leuven Center for Human Genetics and Leuven research Institute for Neuroscience and Disease (LIND), Leuven, Belgium ; VIB Center for the Biology of Disease, Leuven, Belgium.
Bart
B
De Strooper
KU Leuven Center for Human Genetics and Leuven research Institute for Neuroscience and Disease (LIND), Leuven, Belgium ; VIB Center for the Biology of Disease, Leuven, Belgium.
Ina
I
Tesseur
D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D059748:Proteolysis; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D019390:Arrestins; D000071557:beta-Arrestins; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000242:Cyclic AMP; D019061:src-Family Kinases; D047390:Casein Kinase II; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D010738:Type C Phospholipases; D053829:Amyloid Precursor Protein Secretases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases