5-HT₄ receptor stimulation leads to soluble AβPPα production through MMP-9 upregulation.

Serotonin 4 (5-HT4) receptor signaling does not only have the physiological function of improving cognition, but might also be helpful in the therapy of Alzheimer's disease (AD) through regulation of the production of soluble amyloid-beta protein precursor alpha (sA beta PP alpha). To analyze the relationship between 5-HT4 receptor signaling and sA beta PP alpha production, we stably transfected H4 cells with A beta PP and 5-HT4 receptor (H4/A beta PP/5-HT4 cells). We found that 24-h incubation with the 5-HT4 receptor agonist RS-67333 upregulates matrix metalloproteinase-9 (MMP-9). Furthermore, MMP-9 overexpression enhanced sA beta PP alpha levels, whereas knockdown with MMP-9 siRNA decreased sA beta PP alpha levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-beta peptide (A beta) deposition, there was an increase in hippocampal levels of sA beta PP alpha, C-terminal fragment alpha, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, A beta(40). Taken all together, these experiments demonstrate that 5-HT4 receptor stimulation induces expression of MMP-9 which cleaves A beta PP through alpha-secretase-like activity, leading to an increase of sA beta PP alpha levels and a reduction of A beta load.