Efficacy of Chronic Paroxetine Treatment in Mitigating Amyloid Pathology and Microgliosis in APP SWE /PS1 ΔE9 Transgenic Mice

Abstract

Background:

Modulation of serotonergic signaling by treatment with selective serotonin reuptake inhibitors (SSRIs) has been suggested to mitigate amyloid-β (Aβ) 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 Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of 18-month-old APP_swe/PS1_ΔE9 mice.

Methods:

Plaque-bearing APP_swe/PS1_ΔE9 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 [³H]DASB-binding in wildtype mice. Additionally, 5,7-dihydroxytryptamine was administered to 9-month-old APP_swe/PS1_ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ₄₂/Aβ₄₀ 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_ΔE9 mice. The treatment had no effect on the Aβ plaque load (p = 0.39), the number and size of plaques, or the Aβ plaque-induced increases in microglial numbers in the dentate gyrus. Three months of serotonin depletion did not significantly impact the Aβ plaque load or Aβ₄₂/Aβ₄₀ ratio in APP_swe/PS1_ΔE9 mice at 12 months.

Conclusion:

Our results show that chronic treatment with the SSRI paroxetine does not mitigate Aβ pathology and Aβ plaque-induced microgliosis in the hippocampus of APP_swe/PS1_ΔE9 mice.