Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.
Neurochem Int. 2019 Jan;122:31-37. doi: 10.1016/j.neuint.2018.10.022. Epub 2018 Oct 28.
Currently, no treatments exist that are able to directly treat against Alzheimer's disease (AD), and we are facing an inevitable increase in the near future of the amount of patients who will suffer from AD. Most animal models of AD are limited by not being able to recapitulate the entire pathology of AD. Recently an AD model in zebrafish was established by using the protein phosphatase 2A inhibitor, okadaic acid (OKA). Administering OKA to zebrafish was able to recapitulate most of the neuropathology associated with AD. Therefore, providing a drug discovery model for AD that is also time and cost efficient. This study was designed to investigate the effects of GSK3β inhibition by 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8) on this newly developed AD model. Fish were divided into 4 groups and each group received a different treatment. The fish were divided into a control group, a group treated with 1 μM TDZD-8 only, a group treated with 1 μM TDZD-8 + 100 nM OKA, and a group treated with 100 nM OKA only. Administering the GSK3β inhibitor to zebrafish concomitantly with OKA proved to be protective. TDZD-8 treatment reduced the mortality rate, the ratio of active: inactive GSK3β, pTau (Ser199), and restored PP2A activity. This further corroborates the use of GSKβ inhibitors in the treatment against AD and bolsters the use of the OKA-induced AD-like zebrafish model for drug discovery.
目前，尚无能够直接针对阿尔茨海默病（AD）进行治疗的方法，而我们即将面临 AD 患者数量的不可避免增加。大多数 AD 动物模型都存在无法重现 AD 全部病理学的局限性。最近，通过使用蛋白磷酸酶 2A 抑制剂冈田酸（OKA），建立了一种 AD 斑马鱼模型。向斑马鱼中施用 OKA 能够重现与 AD 相关的大多数神经病理学。因此，这种 AD 模型为 AD 药物发现提供了一种既省时又省钱的方法。本研究旨在探讨 GSK3β 抑制剂 4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）对这种新开发的 AD 模型的影响。将鱼分为 4 组，每组接受不同的处理。鱼被分为对照组、仅用 1 μM TDZD-8 处理的组、用 1 μM TDZD-8+100 nM OKA 处理的组和仅用 100 nM OKA 处理的组。同时向斑马鱼施用 GSK3β 抑制剂和 OKA 被证明具有保护作用。TDZD-8 处理降低了死亡率、活性：非活性 GSK3β、pTau（Ser199）的比例，并恢复了 PP2A 活性。这进一步证实了 GSKβ 抑制剂在 AD 治疗中的应用，并支持使用 OKA 诱导的 AD 样斑马鱼模型进行药物发现。
