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

Mithula Sivasaravanaparan, Louise Ørum Olesen, Maurizio Severino, Maurizio Christian Ulrich von Linstow, Kate Lykke Lambertsen, Jan Bert Gramsbergen, Jørgen Hasselstrøm, Athanasios Metaxas, Ove Wiborg, Bente Finsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

3 Citations (Scopus)

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/PS1 ΔE9 mice.

METHODS: Plaque-bearing APPswe/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 APPswe/PS1 ΔE9 mice, to examine the effect of serotonin depletion on Aβ pathology. Aβ pathology was evaluated by Aβ plaque load estimation and the Aβ 42/Aβ 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 APPswe/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 Aβ 42/Aβ 40 ratio in APPswe/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 APPswe/PS1 ΔE9 mice.

Original languageEnglish
JournalJournal of Alzheimer's Disease
Volume87
Issue number2
Pages (from-to)685-699
Number of pages15
ISSN1387-2877
DOIs
Publication statusPublished - 2022

Keywords

  • Cerebral amyloidosis
  • chronic paroxetine treatment
  • hippocampus
  • microgliosis
  • neurogenesis
  • serotonin selective reuptake inhibitors
  • serotonin transporter occupancy
  • stereology
  • Y-maze
  • Humans
  • Paroxetine/pharmacology
  • Presenilin-1/genetics
  • Serotonin Plasma Membrane Transport Proteins/genetics
  • Selective Serotonin Reuptake Inhibitors/pharmacology
  • Amyloid
  • Alzheimer Disease/complications
  • Amyloid beta-Peptides/metabolism
  • Disease Models, Animal
  • Serotonin
  • Mice, Transgenic
  • Plaque, Amyloid/drug therapy
  • Animals
  • Amyloid beta-Protein Precursor/genetics
  • Amyloidosis
  • Mice

Fingerprint

Dive into the research topics of 'Efficacy of Chronic Paroxetine Treatment in Mitigating Amyloid Pathology and Microgliosis in APPSWE/PS1ΔE9 Transgenic Mice'. Together they form a unique fingerprint.

Cite this