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

ABSTRACT

INTRODUCTION: Treatment with selective serotonin reuptake inhibitors has been suggested to mitigate amyloid-ß (Aß) 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 Aß pathology in plaque-bearing double-transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)ΔE9 mutants. In addition, we addressed whether serotonin depletion affects Aß pathology. Treatments were assessed by measurement of serotonin transporter occupancy and high-performance liquid chromatography. The effect of paroxetine on Aß pathology was evaluated by stereological plaque load estimation and Aß42/Aß40 ratio by enzyme-linked immunosorbent assay. RESULTS: Contrary to our hypothesis, paroxetine therapy did not mitigate Aß pathology, and depletion of brain serotonin did not exacerbate Aß 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 Aß pathology. The severe adverse effect of paroxetine may discourage its use for disease-modifying purposes in Alzheimer's disease.