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Efficacy of Chronic Paroxetine Treatment in Mitigating Amyloid Pathology and Microgliosis in APPSWE/PS1ΔE9 Transgenic Mice

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  • Mithula Sivasaravanaparan, Syddansk Universitet
  • ,
  • Louise Ørum Olesen, Aarhus Universitet
  • ,
  • Maurizio Severino, Syddansk Universitet
  • ,
  • Christian Ulrich Von Linstow, Syddansk Universitet
  • ,
  • Kate Lykke Lambertsen, Syddansk Universitet
  • ,
  • Jan Bert Gramsbergen, Syddansk Universitet
  • ,
  • Jørgen Hasselstrøm
  • Athanasios Metaxas, Syddansk Universitet, European University Cyprus
  • ,
  • Ove Wiborg, Aalborg Universitet
  • ,
  • Bente Finsen, Syddansk Universitet

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.

TidsskriftJournal of Alzheimer's Disease
Sider (fra-til)685-699
Antal sider15
StatusUdgivet - maj 2022

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