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

J Alzheimers Dis. 2022;87(2):685-699. doi: 10.3233/JAD-220019.

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.

Keywords: Cerebral amyloidosis; Y-maze; chronic paroxetine treatment; hippocampus; microgliosis; neurogenesis; serotonin selective reuptake inhibitors; serotonin transporter occupancy; stereology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / complications
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / genetics
  • Amyloid
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloidosis*
  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Paroxetine / pharmacology
  • Paroxetine / therapeutic use
  • Plaque, Amyloid / drug therapy
  • Plaque, Amyloid / pathology
  • Presenilin-1 / genetics
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Selective Serotonin Reuptake Inhibitors / therapeutic use
  • Serotonin
  • Serotonin Plasma Membrane Transport Proteins / genetics

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Paroxetine