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5-HT₄ Receptor Stimulation Leads to Soluble AβPPα Production Through MMP-9 Upregulation

Hashimoto, Gakuji; Sakurai, Mikako; Teich, Andrew Franklin; Saeed, Faisal; Aziz, Fahad; Arancio, Ottavio

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 sAβPPαlevels, whereas knockdown with MMP-9 siRNA decreased sAβPPαlevels. When RS-67333 was injected for 10 days in Tg2576 mice, a model of amyloid-βpeptide (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.


Also Published In

Journal of Alzheimer's Disease

More About This Work

Academic Units
Pathology and Cell Biology
Published Here
May 6, 2014