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Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatmen...

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Autores principales: von Linstow, Christian Ulrich, Waider, Jonas, Grebing, Manuela, Metaxas, Athanasios, Lesch, Klaus Peter, Finsen, Bente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596844/
https://www.ncbi.nlm.nih.gov/pubmed/28899417
http://dx.doi.org/10.1186/s13195-017-0298-y
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author von Linstow, Christian Ulrich
Waider, Jonas
Grebing, Manuela
Metaxas, Athanasios
Lesch, Klaus Peter
Finsen, Bente
author_facet von Linstow, Christian Ulrich
Waider, Jonas
Grebing, Manuela
Metaxas, Athanasios
Lesch, Klaus Peter
Finsen, Bente
author_sort von Linstow, Christian Ulrich
collection PubMed
description BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APP(swe)/PS1(ΔE9) (APP/PS1) mouse model of AD. METHODS: We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. RESULTS: Amyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. CONCLUSIONS: Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-017-0298-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-55968442017-09-15 Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice von Linstow, Christian Ulrich Waider, Jonas Grebing, Manuela Metaxas, Athanasios Lesch, Klaus Peter Finsen, Bente Alzheimers Res Ther Research BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APP(swe)/PS1(ΔE9) (APP/PS1) mouse model of AD. METHODS: We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. RESULTS: Amyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation. CONCLUSIONS: Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-017-0298-y) contains supplementary material, which is available to authorized users. BioMed Central 2017-09-12 /pmc/articles/PMC5596844/ /pubmed/28899417 http://dx.doi.org/10.1186/s13195-017-0298-y Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
von Linstow, Christian Ulrich
Waider, Jonas
Grebing, Manuela
Metaxas, Athanasios
Lesch, Klaus Peter
Finsen, Bente
Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title_full Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title_fullStr Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title_full_unstemmed Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title_short Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice
title_sort serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage alzheimer’s-like disease in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596844/
https://www.ncbi.nlm.nih.gov/pubmed/28899417
http://dx.doi.org/10.1186/s13195-017-0298-y
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