Amyloid β 1–42 (Aβ) protein aggregation is considered one of the main triggers of Alzheimer’s disease (AD). In this study, we examined the anti-amyloidogenic activity of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) and its neuroprotective potential against the Aβ toxicity. By performing the Thioflavin T fluorescence assay, Western blotting analyses, and Circular Dichroism experiments, we found that ISOAC1 was able to reduce the Aβ aggregation and conformational transition towards β-sheet structures. Interestingly, studies revealed that ISOAC1 was able to bind to both the monomer and a pentameric protofibril of Aβ, establishing a hydrophobic interaction with the PHE19 residue of the Aβ KLVFF motif. analyses on primary cortical neurons showed that ISOAC1 counteracted the increase of intracellular Ca levels and decreased the Aβ-induced toxicity, in terms of mitochondrial activity reduction and increase of reactive oxygen species production. In addition, confocal microscopy analyses showed that ISOAC1 was able to reduce the Aβ intraneuronal accumulation. Collectively, our results clearly show that ISOAC1 exerts a neuroprotective effect by reducing the Aβ aggregation and toxicity, hence emerging as a promising compound for the development of new Aβ-targeting therapeutic strategies for AD treatment.

中文翻译：

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3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1)作为一种新分子能够抑制β淀粉样蛋白聚集和神经毒性

β 淀粉样蛋白 1–42 (Aβ) 蛋白聚集被认为是阿尔茨海默病 (AD) 的主要诱因之一。在这项研究中，我们检测了异吲哚酮衍生物 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) 的抗淀粉样蛋白生成活性及其对抗 Aβ 毒性的神经保护潜力。通过硫磺素 T 荧光测定、蛋白质印迹分析和圆二色性实验，我们发现 ISOAC1 能够减少 Aβ 聚集和向 β-折叠结构的构象转变。有趣的是，研究表明 ISOAC1 能够结合 Aβ 的单体和五聚原纤维，与 Aβ KLVFF 基序的 PHE19 残基建立疏水相互作用。对原代皮质神经元的分析表明，ISOAC1 通过减少线粒体活性和增加活性氧生成来抵消细胞内 Ca 水平的增加并降低 Aβ 诱导的毒性。此外，共聚焦显微镜分析表明 ISOAC1 能够减少 Aβ 神经元内的积累。总的来说，我们的结果清楚地表明 ISOAC1 通过减少 Aβ 聚集和毒性来发挥神经保护作用，因此成为开发新的 Aβ 靶向 AD 治疗策略的有前途的化合物。