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

Date Published: September 12, 2017

Publisher: BioMed Central

Author(s): Christian Ulrich von Linstow, Jonas Waider, Manuela Grebing, Athanasios Metaxas, Klaus Peter Lesch, Bente Finsen.


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 APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.

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.

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.

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.

The online version of this article (doi:10.1186/s13195-017-0298-y) contains supplementary material, which is available to authorized users.

Partial Text

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterised by amyloid and tau pathology, as well as a progressive decay of brain circuitry, leading to cognitive impairment especially affecting memory [1]. In addition to the cholinergic degenerative damage in AD [2], deterioration of the serotonergic (5-HTergic) system has also attracted attention for its involvement in AD presentation because the 5-HTergic system is involved in the regulation of mood [3] and in memory function [4]. Changes of the 5-HTergic system in AD include loss of raphe neurons [5, 6], reduced activity of tryptophan hydroxylase [7] and a reduction in cortical levels of serotonin (5-HT) [8, 9]. It has been suggested that AD pathology may even originate in the brainstem, which contains the 5-HTergic neurons clustered in the raphe nuclei [10, 11].

Recently, it was reported that SSRI treatment attenuates plaque pathology in the APP/PS1 mouse model of familial AD [24, 32, 33]. To further test this hypothesis, we treated 3-month-old APP/PS1 mice with the more selective SSRI escitalopram [34] for a period of 6 months at a dosage of 5 mg/kg/day. This dosage was predicted to inhibit SERT in the therapeutic range, as confirmed by a SERT occupancy assay. We did not observe any changes in body weight, although this is a common side effect of SSRI treatment in both humans and rodents [35–37].

Our observations do not support chronic escitalopram treatment as a strategy for anti-Aβ therapy, because we observed significant increases in the levels of insoluble Aβ in the neocortex of APP/PS1 mice. 5-HTergic deafferentation of the cortex did not affect the production of Aβ peptides. However, we did observe a reduction in sAPPα levels. Overall, our findings do not support modulation of the 5-HTergic system with the purpose of reducing Aβ levels in prodromal and early AD.




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