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

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

Established amyloid‐β pathology is unaffected by chronic treatment with the selective serotonin reuptake inhibitor paroxetine

“…citalopram increase seizure activity and mortality of AD transgenic mice. Importantly, we did not observe any mortality in the APP/PS1 mice treated with escitalopram (5 mg/kg/day per os ) from 3 to 9 months of age [31] . It is also possible that chronic SSRI treatment, especially when administered i.p.…”

“…was sufficient to mitigate plaque load; however, as acknowledged by the authors, the plaque load was not quantified [22] . In contrast, a study from our own group showed no or minor effect on the Aβ levels in neocortex and hippocampus in APP/PS1 mice treated from 3 to 9 months of age with escitalopram in a dose of 5 mg/kg/day per os , leading to ≈80% occupancy of SERT [31] . This suggests that the differences in results cannot simply be explained by differences in the time of treatment start, but that other factors, such as sex, genetic background, and type of SSRI should be taken into consideration.…”

“…Neurotoxin: To destroy 5-HT fibers and neurons, 5,7-dihydroxytryptophan (5,7-DHT) was stereotaxically injected into the lateral ventricles of 9-month-old male APP/PS1 and Wt mice ( Table 1 ), as described elsewhere [31] , but injecting a total dose of 80 μg 5,7-DHT. Mice with unsuccessful lesions, as determined by the measurement of 5-HT in neocortical tissues, were excluded from statistical analysis (Danish Veterinary & Food Administration: J.no.…”

Neuroinflammation and amyloid-beta 40 are associated with reduced serotonin transporter (SERT) activity in a transgenic model of familial Alzheimer’s disease

“…Acute SSRI treatment has been shown to immediately reduce the levels of Aβ 40/42 in the brain interstitial fluid of APP swe /PS1 dE9 mice [35], as well as in the cerebrospinal fluid of healthy human volunteers [36], supporting a direct association between SERT function and amyloidosis. However, the Aβ-lowering effects of SSRIs have not been reported consistently in humans [37], nor in APP swe /PS1 dE9 mice [38]. Studies on the kinetics of [ 3 H]5-HT uptake in platelets from AD patients have also been inconsistent, reporting decreased V max and K m [39], decreased V max and unaltered K m [40], and cognitive-status-dependent changes in the V max of [ 3 H]5-HT in demented vs. non-demented subjects [41].…”

Sphingolipid metabolism in the pathophysiology and treatment of Alzheimer’s disease

“…Nevertheless, there are inconsistencies. In fact, the long-term effect of escitalopram, an SSRI, administration showed to be inefficient in controlling plaques disease and even is contraindicated [322].…”