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

Abstract

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. 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 Aβ 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 Aβ generation through multiple HTR6-mediated targets, including β-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.

Serotonin, β‐amyloid, and cognition in Parkinson disease

“…Figure 1 provides an overview of our PPMI study cohorts. We categorized serotoninergic medications to include selective serotonin reuptake inhibitors (SSRIs) 21 , serotonin-norepinephrine reuptake inhibitors (SNRIs) 22 , tricyclic antidepressants (TCAs) 17 , bupropion 23 , lithium 24 , and St. John’s Wort 25 given that each of these compounds has been shown to influence serotoninergic neurotransmission. In this cross-sectional baseline study aimed at understanding the influence of serotonin medications on CSF Aβ-42, we categorized subjects as those taking serotonin medications for ≥6 months (n=45) vs. others (n=344).…”

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice

“…Memantine targets glutamatergic transmission by blocking NMDA receptors to decrease excitotoxicity (Molinuevo et al, 2005; Olivares et al, 2012). Other neurotransmitter systems such as dopamine (Martorana and Koch, 2014; Nobili et al, 2017) and serotonin (Li et al, 2017; Vakalopoulos, 2017) may be involved in the progression of AD. There is also growing evidence that tryptophan is involved in the pathogenesis of AD independently of its role as the serotonin precursor.…”

A novel rhamnoside derivative PL402 up-regulates matrix metalloproteinase 3/9 to promote Aβ degradation and alleviates Alzheimer’s-like pathology

“…On the next day, the cells were transfected with shRNA constructs and packaging plasmids. The protocol of this transfection was followed by the calcium phosphate transfection procedure [54]. The cells were further cultured for 48 and 72 h to produce the lentivirus, and the culture medium were then filtrated through 0.45-μm filters.…”

“…was determined used the RT-qPCR. The mentioned protocols referred to the previously reported article [54].…”