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A tricyclic antidepressant, amoxapine, reduces amyloid-? generation through multiple serotonin receptor 6-mediated targets.

ABSTRACT: Alzheimer's disease (AD) is a major and devastating neurodegenerative disease, and the amyloid-? (A?) hypothesis is still the central theory for AD pathogenesis. Meanwhile, another major mental illness, depression, is one of the risk factors for AD. From a high-throughput screening (HTS), amoxapine, a typical secondary amine tricyclic antidepressant (TCA), was identified to reduce A? production. A follow-up investigation on antidepressants showed that most of the TCAs harbour similar activity. Previous studies have indicated that TCAs improve cognitive function in AD mouse models as well as in preliminary clinical data; however, the underlying mechanism is controversial, and the effect on A? is elusive. Thus, we developed a secondary screening to determine the molecular target of amoxapine, and serotonin receptor 6 (HTR6) was identified. Knockdown of HTR6 reduced the amoxapine's effect, while the HTR6 antagonist SB258585 mimicked the activity of amoxapine. Further mechanistic study showed that amoxapine and SB258585 reduced A? generation through multiple HTR6-mediated targets, including ?-arrestin2 and CDK5. Taken together, our study suggests that amoxapine, though no longer a first-line drug for the treatment of depression, may be beneficial for AD and further structural modification of TCAs may lead to desirable therapeutic agents to treat both AD and depression.

SUBMITTER: Li X

PROVIDER: S-EPMC5504036 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A tricyclic antidepressant, amoxapine, reduces amyloid-β generation through multiple serotonin receptor 6-mediated targets.

Li Xiaohang X Wang Qinying Q Hu Tingting T Wang Ying Y Zhao Jian J Lu Jing J Pei Gang G

Scientific reports 20170710 1

Alzheimer's disease (AD) is a major and devastating neurodegenerative disease, and the amyloid-β (Aβ) hypothesis is still the central theory for AD pathogenesis. Meanwhile, another major mental illness, depression, is one of the risk factors for AD. From a high-throughput screening (HTS), amoxapine, a typical secondary amine tricyclic antidepressant (TCA), was identified to reduce Aβ production. A follow-up investigation on antidepressants showed that most of the TCAs harbour similar activity. P ...[more]

PMID: 28694424

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Project description:ObjectiveSerotoninergic neurotransmission may modulate β-amyloid peptide (Aβ) metabolism through upregulation of α-secretase. Early Parkinson disease (PD) shows variable serotoninergic denervation, which may impact Aβ deposition.MethodsWe conducted 3 analyses to explore associations between serotoninergic neurotransmission and cerebral Aβ burden in PD. The first was a cross-sectional imaging study of PD subjects (n = 23) using the serotoninergic transporter positron emission tomography (PET) ligand [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and amyloid PET Pittsburgh compound B ([11 C]PiB). The second was a baseline study of Parkinson's Progression Markers Initiative (PPMI) subjects exploring the influence of serotoninergic medications on cerebrospinal fluid (CSF) Aβ-42 levels (n = 389), controlling for age, sex, Geriatric Depression Scale, disease duration, and education. Third, we fit an interval censored proportional hazard model with longitudinal PPMI data (n = 367) to test whether serotoninergic medication use associates with reduced risk of PD cognitive decline, defined as time to reach a Montreal Cognitive Assessment score ≤ 20, adjusting for baseline caudate dopamine transporter [123 I]ioflupane single photon emission computed tomography and CSF Aβ-42 levels.ResultsSerotoninergic DASB distribution volume ratio (DVR) inversely associated with PiB DVR in the cerebral cortex (Pearson r = -0.478, p = 0.021) but not the striatum (r = -0.264, p = 0.224). In the baseline PPMI analysis, serotoninergic medication use for ≥6 months associated with a lower level of CSF Aβ-42 (t = -2.20, p = 0.029). In the longitudinal PPMI model, baseline serotoninergic medication use associated with a reduced risk of cognitive decline (t = -2.03, p = 0.043) after controlling for covariates.InterpretationCortical Aβ burden in PD associates inversely with serotoninergic innervation. Serotoninergic medications may alter Aβ metabolism and reduce the risk of PD cognitive decline. Ann Neurol 2018;83:994-1002.

Dataset Information

A tricyclic antidepressant, amoxapine, reduces amyloid-? generation through multiple serotonin receptor 6-mediated targets.

Publications

A tricyclic antidepressant, amoxapine, reduces amyloid-β generation through multiple serotonin receptor 6-mediated targets.

Similar Datasets

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