Abstract
BackgroundDysfunction 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.MethodsWe 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.ResultsAmyloid-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.ConclusionsBecause 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.
Highlights
Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD)
Dosing confirmation studies Given that escitalopram is approximately twice as potent as citalopram [31] and that treatment of Amyloid precursor protein (APP)/ PS1 mice with 8 mg/kg/day citalopram per os was previously reported to reduce Aβ load in APP/PS1 mice [24], we aimed to treat animals with escitalopram at a dose of 5 mg/kg/day in the drinking water
The daily water intake of adult APP/ PS1 mice was monitored over a period of 4 weeks (n = 5; data not shown)
Summary
Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). 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. 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]. The effect of 5-HT augmentation therapy on cognitive function in patients with AD has been examined in placebo-controlled studies with use of selective serotonin reuptake inhibitors (SSRIs) [12,13,14,15], but these studies have had limited success [16]. Reducing levels of 5-HT by acute tryptophan depletion worsens cognitive function in patients with AD [19]
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