State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Sci Rep. 2017 Jul 10;7(1):4983. doi: 10.1038/s41598-017-04144-3.
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.
阿尔茨海默病（AD）是一种主要且具有破坏性的神经退行性疾病，淀粉样蛋白-β（Aβ）假说仍然是 AD 发病机制的核心理论。同时，另一种主要的精神疾病——抑郁症，也是 AD 的风险因素之一。通过高通量筛选（HTS），发现阿莫沙平（amoxapine）——一种典型的仲胺三环抗抑郁药（TCA），可以减少 Aβ的产生。对抗抑郁药的后续研究表明，大多数 TCA 具有类似的活性。先前的研究表明，TCAs 可改善 AD 小鼠模型以及初步临床数据中的认知功能；然而，其潜在机制存在争议，对 Aβ的影响也难以捉摸。因此，我们进行了二次筛选以确定阿莫沙平的分子靶标，发现了 5-羟色胺受体 6（HTR6）。HTR6 的敲低降低了阿莫沙平的效果，而 HTR6 拮抗剂 SB258585 则模拟了阿莫沙平的活性。进一步的机制研究表明，阿莫沙平和 SB258585 通过多种 HTR6 介导的靶点减少 Aβ的产生，包括β-arrestin2 和 CDK5。综上所述，我们的研究表明，尽管阿莫沙平不再是治疗抑郁症的一线药物，但它可能对 AD 有益，进一步对 TCA 的结构修饰可能会产生治疗 AD 和抑郁症的理想治疗药物。
