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

Maurizio Severino; Mithula Sivasaravanaparan; Louise Ø Olesen; Christian U von Linstow; Athanasios Metaxas; Elena V Bouzinova; Asif Manzoor Khan; Kate L Lambertsen; Alicia A Babcock; Jan Bert Gramsbergen; Ove Wiborg; Bente Finsen

doi:10.1016/j.trci.2018.04.005

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

Alzheimers Dement (N Y). 2018 May 24:4:215-223. doi: 10.1016/j.trci.2018.04.005. eCollection 2018.

Authors

Maurizio Severino¹, Mithula Sivasaravanaparan¹, Louise Ø Olesen², Christian U von Linstow¹, Athanasios Metaxas¹, Elena V Bouzinova², Asif Manzoor Khan¹, Kate L Lambertsen^{1

3

4}, Alicia A Babcock¹, Jan Bert Gramsbergen^{1

4}, Ove Wiborg^{2

5}, Bente Finsen^{1

4}

Affiliations

¹ Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
² Center of Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.
³ Department of Neurology, Odense University Hospital, Odense, Denmark.
⁴ BRIDGE - Brain Research -Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁵ Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.

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 Aβ₄₂/Aβ₄₀ 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.

Keywords: 5,7-dihydroxytryptamine; Alzheimer's disease; Autoradiography; Cerebral amyloidosis; Monoamine; Neocortex; SERT occupancy; Selective serotonin reuptake inhibitor; Serotonin; Stereology; Transgenic mouse model; [3H]DASB.