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.
- Cerebral amyloidosis
- chronic paroxetine treatment
- serotonin selective reuptake inhibitors
- serotonin transporter occupancy
- Serotonin Plasma Membrane Transport Proteins/genetics
- Selective Serotonin Reuptake Inhibitors/pharmacology
- Alzheimer Disease/complications
- Amyloid beta-Peptides/metabolism
- Disease Models, Animal
- Mice, Transgenic
- Plaque, Amyloid/drug therapy
- Amyloid beta-Protein Precursor/genetics