5-HT 4 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-β protein precursor alpha (sAβPPα). To analyze the relationship between 5-HT₄ receptor signaling and sAβPPα production, we stably transfected H4 cells with AβPP and 5-HT₄ receptor (H4/AβPP/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 sAβPPα levels, whereas knockdown with MMP-9 siRNA decreased sAβPPα levels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-β peptide (Aβ) deposition, there was an increase in hippocampal levels of sAβPPα, C-terminal fragment α, and MMP-9, as well as a decrease in hippocampal senile plaque number and levels of the 40 amino acid peptide, Aβ₄₀. Taken all together, these experiments demonstrate that 5-HT₄ receptor stimulation induces expression of MMP-9 which cleaves AβPP through α-secretase-like activity, leading to an increase of sAβPPα levels and a reduction of Aβ load.