Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model

Abstract

Rationale:Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into amyloid-β (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 ESC 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 two-photon imaging to assess changes in brain interstitial fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/PS1 mouse model of Alzheimer’s disease treated with vehicle or ESC. We also chronically treated mice with ESC to determine the effect on plaques histologically.Results:ESC acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of ESC significantly reduced plaque load by 28% and 34% at 2.5 mg/day and 5 mg/day, respectively. ESC at 5mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time.Conclusions:ESC significantly reduced Aβ in mice similar to previous findings in humans treated with acute dosing of an SSRI.

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

“…SSRIs, which increase serotonin levels in the brain, show promise for reduction of Aβ accumulation in both the brain and CSF. Studies in APP/PS1 transgenic mice showed that the SSRI citalopram caused a 50% reduction in brain amyloid plaque load, and escitalopram, citalopram's S-isomer, reduced interstitial fluid Aβ by 25% 81,82 . A controlled clinical trial of cognitively normal adults showed that escitalopram could decrease CSF Aβ42 levels in humans, with a difference of 11.1% between the control and treatment groups 83 .…”

Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

“…There are numerous reports that antidepressants from the SSRI group exhibit neuroprotective effects with a diverse mechanism of action. Preclinical and clinical studies indicate beneficial effects on cognitive function [ 14 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ]. Furthermore, literature data indicate that SSRIs “ increase neurotrophic factors including brain-derived neurotrophic factor, promote neurogenesis in the hippocampus, and reduce levels of toxic Aβ ” [ 124 ].…”

“…Another drug being considered as a candidate for the treatment of AD is escitalopram, the most specific selective serotonin reuptake inhibitor [ 119 ].…”

“…At a dose of 2.5 mg/kg, a 28% reduction was achieved, whereas at a dose of 5 mg/kg, the reduction was 34%. Furthermore, the authors found that escitalopram at a dose of 5 mg/kg, although not removing existing plaques, stopped their growth [ 119 ].…”

Opportunities for Drug Repurposing of Serotonin Reuptake Inhibitors: Potential Uses in Inflammation, Infection, Cancer, Neuroprotection, and Alzheimer’s Disease Prevention

“…Serotonin infusion into the brain decreases Aβ by reducing its production. Cirrito et al found that citalopram and escitalopram administered to mice acutely decreased Aβ levels by 25 % within eight hours while chronic administration decreased plaque deposition even further by increasing α-secretase activity [56][57][58][59]. Chronic reduction in Aβ levels lowers the risk of accumulating toxic conformations that produce amyloid plaques.…”