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 language | English |
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Journal | Alzheimer's & Dementia: Translational Research & Clinical Interventions |
Volume | 4 |
Pages (from-to) | 215-223 |
ISSN | 2352-8737 |
DOIs | |
Publication status | Published - 1. Jan 2018 |
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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
}
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 journal › Journal article › Research › peer-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 -