Efficacy of Chronic Paroxetine Treatment in Mitigating Amyloid Pathology and Microgliosis in APP(SWE)/PS1(Delta E9) Transgenic Mice

Background: Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-beta (A beta) pathology in Alzheimer's disease, in addition to exerting an anti-depressant action. Objective: To investigate the efficacy of chronic treatment with the SSRI paroxetine, in mitigating A beta pathology and A beta plaque-induced microgliosis in the hippocampus of 18-month-old APP(swe)/PS1(Delta E9) mice. Methods: Plaque-bearing APP(swe)/PS1(Delta E9) and wildtype mice were treated with paroxetine per os at a dose of 5 mg/kg/day, from 9 to 18 months of age. The per os treatment was monitored by recording of the body weights and serum paroxetine concentrations, and by assessment of the serotonin transporter occupancy by [H-3]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APP(swe)/PS1(Delta E9) mice, to examine the effect of serotonin depletion on A beta pathology. A beta pathology was evaluated by A beta plaque load estimation and the A beta(42)/A beta(40) ratio by ELISA. Results: Paroxetine treatment led to > 80% serotonin transporter occupancy. The treatment increased the body weight of wildtype mice, but not of APP(swe)/PS1(Delta E9) mice. The treatment had no effect on the A beta plaque load (p = 0.39), the number and size of plaques, or the A beta plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the A beta plaque load or A beta(42)/A beta(40) ratio in APP(swe)/PS1(Delta E9) mice at 12 months. Conclusion: Our results show that chronic treatment with the SSRI paroxetine does not mitigate A beta pathology and A beta plaque-induced microgliosis in the hippocampus of APP(swe)/PS1(Delta E9) mice.