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

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 APP swe/PS1 ΔE9 mice. Methods: Plaque-bearing APP swe/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 APP swe/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 APP swe/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 APP swe/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 APP swe/PS1 ΔE9 mice.

Antidepressant sertraline increases thioflavin-S and Congo red deposition in APPswe/PSEN1dE9 transgenic mice

“…In this section, we review other studies and discuss the impact of chronic SSRI treatment on the formation of β-amyloid, considering potential outcomes such as protective effects, no discernible impact, or an increase in plaque load. Consistent with our results, Severino et al and Sivasaravanaparan et al showed that chronic paroxetine therapy, administered at a dosage of 10 mg/kg/day in drinking water, elevated mortality rates in APP/PSEN1 transgenic mice aged 9–18 months ( Severino et al, 2018 ; Sivasaravanaparan et al, 2022 ). Notably, a substantial improvement in survival outcomes was observed when the dosage was reduced to 5 mg/kg/day during the same age range.…”

Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis

“… Morgese et al (2021) reported that serotonin levels were decreased in Aβ-injected rats which was established as a rat model mimicking the early phase of AD. In another recent experiment ( Sivasaravanaparan et al, 2022 ), nevertheless, chronic treatment with paroxetine—a selective serotonin reuptake inhibitor, failed to mitigate Aβ pathology and microgliosis in APPSWE/PS1ΔE9 mice. In addition, the serotonin transporter ( SLC6A4 ) which regulates the serotonin concentrations and serves as the target of selective serotonin reuptake inhibitors, might be associated with AD risks ( Polito et al, 2011 ; Yamazaki et al, 2016 ).…”

Anxiety and Alzheimer’s disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models

“…However, there are issues in both consistency and translational ability of SSRIs' effectiveness in reducing AD pathogenesis and improving cognitive and behavioral deficits. In the APP/PS1 model, studies report no change in Aβ deposition, nor cognitive or behavioral measures (Severino et al, 2018;Sivasaravanaparan et al, 2022;see Mdawar et al, 2020; for a review; refer to Table 9). Although treatments with SSRIs varied in AD rodent models, given that treatment with SSRIs worked in a subsection of AD animal models, both in reducing AD 10.3389/fnagi.…”