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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Abstract

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
Volume4
Pages (from-to)215-223
ISSN2352-8737
DOIs
Publication statusPublished - 1. Jan 2018

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Paroxetine
Serotonin Uptake Inhibitors
Pathology
Presenilin-1
Alzheimer Disease
Serotonin Plasma Membrane Transport Proteins
High Pressure Liquid Chromatography

Keywords

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

Cite this

Severino, Maurizio ; Sivasaravanaparan, Mithula ; Olesen, Louise Ørum ; von Linstow, Christian Ulrich ; Metaxas, Athanasios ; Bouzinova, Elena ; Khan, Asif Manzoor ; Lambertsen, Kate Lykke ; Babcock, Alicia ; Gramsbergen, Jan Bert ; Wiborg, Ove ; Finsen, Bente. / Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine. In: Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2018 ; Vol. 4. pp. 215-223.
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abstract = "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.",
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author = "Maurizio Severino and Mithula Sivasaravanaparan and Olesen, {Louise {\O}rum} and {von Linstow}, {Christian Ulrich} and Athanasios Metaxas and Elena Bouzinova and Khan, {Asif Manzoor} and Lambertsen, {Kate Lykke} and Alicia Babcock and Gramsbergen, {Jan Bert} and Ove Wiborg and Bente Finsen",
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Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine. / Severino, Maurizio ; Sivasaravanaparan, Mithula; Olesen, Louise Ørum; von Linstow, Christian Ulrich; Metaxas, Athanasios; Bouzinova, Elena; Khan, Asif Manzoor; Lambertsen, Kate Lykke; Babcock, Alicia; Gramsbergen, Jan Bert; Wiborg, Ove; Finsen, Bente.

In: Alzheimer's & Dementia: Translational Research & Clinical Interventions, Vol. 4, 01.01.2018, p. 215-223.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Established amyloid-β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine

AU - Severino, Maurizio

AU - Sivasaravanaparan, Mithula

AU - Olesen, Louise Ørum

AU - von Linstow, Christian Ulrich

AU - Metaxas, Athanasios

AU - Bouzinova, Elena

AU - Khan, Asif Manzoor

AU - Lambertsen, Kate Lykke

AU - Babcock, Alicia

AU - Gramsbergen, Jan Bert

AU - Wiborg, Ove

AU - Finsen, Bente

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - 5,7-dihydroxytryptamine

KW - Alzheimer's disease

KW - Autoradiography

KW - Cerebral amyloidosis

KW - Monoamine

KW - Neocortex

KW - SERT occupancy

KW - Selective serotonin reuptake inhibitor

KW - Serotonin

KW - Stereology

KW - Transgenic mouse model

KW - [ H]DASB

U2 - 10.1016/j.trci.2018.04.005

DO - 10.1016/j.trci.2018.04.005

M3 - Journal article

VL - 4

SP - 215

EP - 223

JO - Alzheimer's & Dementia: Translational Research & Clinical Interventions

JF - Alzheimer's & Dementia: Translational Research & Clinical Interventions

SN - 2352-8737

ER -