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 Ø
AU - von Linstow, Christian U
AU - Metaxas, Athanasios
AU - Bouzinova, Elena V
AU - Khan, Asif Manzoor
AU - Lambertsen, Kate L
AU - Babcock, Alicia A
AU - Gramsbergen, Jan Bert
AU - Wiborg, Ove
AU - Finsen, Bente
PY - 2018
Y1 - 2018
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 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 APPswe/PS1ΔE9 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 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 APPswe/PS1ΔE9 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
UR - http://www.scopus.com/inward/record.url?scp=85048457883&partnerID=8YFLogxK
U2 - 10.1016/j.trci.2018.04.005
DO - 10.1016/j.trci.2018.04.005
M3 - Journal article
C2 - 29955664
SN - 1552-5260
VL - 4
SP - 215
EP - 223
JO - Alzheimer's & Dementia
JF - Alzheimer's & Dementia
ER -