Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine

Maurizio Severino, Mithula Sivasaravanaparan, Louise Ørum Olesen, Christian Ulrich von Linstow, Athanasios Metaxas, Elena Bouzinova, Asif Manzoor Khan, Kate Lykke Lambertsen, Alicia Babcock, Jan Bert Gramsbergen, Ove Wiborg, Bente Finsen

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Introduction: Treatment with selective serotonin reuptake inhibitors has been suggested to mitigate amyloid-β (Aβ) pathology in Alzheimer's disease, in addition to an antidepressant mechanism of action. Methods: We investigated whether chronic treatment with paroxetine, a selective serotonin reuptake inhibitor, mitigates Aβ pathology in plaque-bearing double-transgenic amyloid precursor protein (APP) swe/presenilin 1 (PS1) ΔE9 mutants. In addition, we addressed whether serotonin depletion affects Aβ pathology. Treatments were assessed by measurement of serotonin transporter occupancy and high-performance liquid chromatography. The effect of paroxetine on Aβ pathology was evaluated by stereological plaque load estimation and Aβ 42/Aβ 40 ratio by enzyme-linked immunosorbent assay. Results: Contrary to our hypothesis, paroxetine therapy did not mitigate Aβ pathology, and depletion of brain serotonin did not exacerbate Aβ pathology. However, chronic paroxetine therapy increased mortality in APP swe/PS1 ΔE9 transgenic mice. Discussion: Our results question the ability of selective serotonin reuptake inhibitor therapy to ameliorate established Aβ pathology. The severe adverse effect of paroxetine may discourage its use for disease-modifying purposes in Alzheimer's disease.

Original languageEnglish
JournalAlzheimer's & Dementia: Translational Research & Clinical Interventions
Pages (from-to)215-223
Publication statusPublished - 1. Jan 2018


  • 5,7-dihydroxytryptamine
  • Alzheimer's disease
  • Autoradiography
  • Cerebral amyloidosis
  • Monoamine
  • Neocortex
  • SERT occupancy
  • Selective serotonin reuptake inhibitor
  • Serotonin
  • Stereology
  • Transgenic mouse model
  • [ H]DASB


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