Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-ß 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-ß (Aß) 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 Aß pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aß pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aß pathology in the APPswe/PS1ΔE9 (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-ß-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 Aß42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aß40 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 Aß42 and Aß40 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 Aß42 and Aß40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aß pathology.