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Published on: March 16, 2016
Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model
John R Cirrito1, Clare E Wallace2, Ping Yan2
1From the Department of Neurology (J.R.C., T.A.D., W.D.G., B.M.D., D.K., C.M.Y., J.-M.L.), The Knight Alzheimer's Disease Research Center, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO; Center for Neuromodulation in Depression and Stress, Department of Psychiatry (C.E.W., P.Y., Y.I.S.), and Departments of Psychiatry, Radiology, and Neurology (Y.I.S.), University of Pennsylvania, Philadelphia. cirritoj@wustl.edu.
Background:
Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice.
Objectives:
We hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load.
Methods:
We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically.
Results:
Escitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.
Conclusions:
Escitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.
