Affiliations: [a] Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Denmark
| [b] Department of Clinical Medicine, Aarhus University Hospital, Denmark
| [c] Department of Neurology, Odense University Hospital, Odense, Denmark
| [d] Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, Denmark
| [e] Forensic Chemistry Department, Aarhus University, Denmark
| [f] Department of Life Sciences, School of Science, European University Cyprus, Nicosia, Cyprus
| [g] Department of Health Science and Technology, Aalborg University, Denmark
Correspondence:
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Correspondence to: Bente Finsen, Department of Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 25, DK-5000 Odense C, Denmark. Tel.: +45 6550 3990; E-mail: [email protected].
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 APPswe/PS1ΔE9 mice. Methods:Plaque-bearing APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 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 APPswe/PS1ΔE9 mice.
