The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein

The serotonin 5-HT4 receptor has recently gained a lot of attention for its functional roles in central processes such as memory and cognition. In thi s study, we show that activation of the human 5-HT4 (h5-HT4) receptor stimu lates the secretion of the non-amyloidogenic soluble form of the amyloid pr ecursor protein (sAPP alpha). 5-HT enhanced the level of secreted sAPP alph a in a time- and dose-dependent manner in Chinese hamster ovary cells stabl y expressing the h5-HT4(e) receptor isoform. The increase was inhibited by the selective 5-HT4 receptor antagonist, GR113808. The 5-HT4 selective agon ists, prucalopride and renzapride, also increased secreted sAPP alpha in IM R32 human neuroblastoma cells. The stimulatory effect of 5-HT was mimicked by forskolin, a direct activator of adenylyl cyclase, and 8-bromo-cAMP, a m embrane-permeant cAMP analogue. On the contrary, inhibition of protein kina se A (PKA) by H89 potentiated the 5-HT-induced increase in both secreted an d cellular sAPP alpha. This phenomenon involves a novel PKA-independent sti mulatory process that overcomes a PKA-dependent inhibitory one. Finally, ac tivation of the h5-HT4(e) receptor did not modify extracellular amyloid bet a -protein in Chinese hamster ovary cells transfected with the human APP695 . Given the neuroprotective and enhancing memory effects of sAPP alpha, our results may open a new avenue for the treatment of Alzheimer's disease.