Laboratory of Neurophysiology, Department of Physiology, Universidad de Concepción, Concepción, Chile.
The Center for Bioinformatics and Molecular Simulations (CBSM), Universidad de Talca, Talca, Chile.
Neurobiol Dis. 2020 Jul;141:104938. doi: 10.1016/j.nbd.2020.104938. Epub 2020 May 18.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Existent therapies are directed at alleviating some symptoms, but are not effective in altering the course of the disease.
Based on our previous study that showed that an Aβ-interacting small peptide protected against the toxic effects of amyloid-beta peptide (Aβ), we carried out an array of in silico, in vitro, and in vivo assays to identify a molecule having neuroprotective properties.
In silico studies showed that the molecule, referred to as M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine), was able to interact with the Aβ peptide. Additionally, in vitro assays showed that M30 blocked Aβ aggregation, association to the plasma membrane, synaptotoxicity, intracellular calcium, and cellular toxicity, while in vivo experiments demonstrated that M30 induced a neuroprotective effect by decreasing the toxicity of Aβ in the dentate gyrus of the hippocampus and improving the alteration in spatial memory in behavior assays.
Therefore, we propose that this new small molecule could be a useful candidate for the additional development of a treatment against AD since it appears to block multiple steps in the amyloid cascade. Overall, since there are no drugs that effectively block the progression of AD, this approach represents an innovative strategy.
Currently, there is no effective treatment for AD and the expectations to develop an effective therapy are low. Using in silico, in vitro, and in vivo experiments, we identified a new compound that is able to inhibit Aβ-induced neurotoxicity, specifically aggregation, association to neurons, synaptic toxicity, calcium dyshomeostasis and memory impairment induced by Aβ. Because Aβ toxicity is central to AD progression, the inhibition mediated by this new molecule might be useful as a therapeutic tool.
阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病。现有的治疗方法旨在缓解一些症状，但不能有效改变疾病的进程。
基于我们之前的研究表明，一种与 Aβ 相互作用的小肽可以对抗淀粉样β肽（Aβ）的毒性作用，我们进行了一系列的计算机模拟、体外和体内实验，以确定具有神经保护特性的分子。
计算机模拟研究表明，该分子被称为 M30（2-辛基二氢异喹啉-2（1H）-乙胺），能够与 Aβ 肽相互作用。此外，体外实验表明，M30 可阻止 Aβ 聚集、与质膜结合、突触毒性、细胞内钙和细胞毒性，而体内实验表明，M30 通过降低 Aβ 在海马齿状回的毒性和改善行为试验中空间记忆的改变来诱导神经保护作用。
因此，我们提出，这种新的小分子可能是开发治疗 AD 的附加治疗方法的有用候选物，因为它似乎可以阻断淀粉样蛋白级联反应中的多个步骤。总的来说，由于没有药物能够有效阻止 AD 的进展，因此这种方法代表了一种创新策略。
目前，AD 没有有效的治疗方法，开发有效疗法的期望很低。我们通过计算机模拟、体外和体内实验，鉴定出一种新的化合物，它能够抑制 Aβ 诱导的神经毒性，特别是聚集、与神经元结合、突触毒性、钙动态平衡和 Aβ 诱导的记忆损伤。由于 Aβ 毒性是 AD 进展的核心，这种新分子介导的抑制作用可能作为一种治疗工具很有用。
