Huang Shu-Hsiang, Fang Shang-Ting, Yang Chin-Hao, Liou Je-Wen, Chen Yi-Cheng
Department of Medicine, MacKay Medical College, New Taipei City 252, Taiwan.
Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien City 970, Taiwan.
Int J Mol Sci. 2024 Dec 9;25(23):13219. doi: 10.3390/ijms252313219.
Alzheimer's disease (AD) is primarily driven by the formation of toxic amyloid-β (Aβ) aggregates, with Aβ42 being a pivotal contributor to disease pathology. This study investigates a novel agent to mitigate Aβ42-induced toxicity by co-assembling Aβ42 with its G37V variant (Aβ42(G37V)), where Gly at position 37 is substituted with valine. Using a combination of Thioflavin-T (Th-T) fluorescence assays, Western blot analysis, atomic force microscopy (AFM)/transmission electron microscopy (TEM), and biochemical assays, we demonstrated that adding Aβ42(G37V) significantly accelerates Aβ42 aggregation rate and mass while altering the morphology of the resulting aggregates. Consequently, adding Aβ42(G37V) reduces the Aβ42 aggregates-induced cytotoxicity, as evidenced by improved cell viability assays. The possible mechanism for this effect is that adding Aβ42(G37V) reduces the production of reactive oxygen species (ROS) and lipid peroxidation, typically elevated in response to Aβ42, indicating its protective effects against oxidative stress. These findings suggest that Aβ42(G37V) could be a promising candidate for modulating Aβ42 aggregation dynamics and reducing its neurotoxic effects, providing a new avenue for potential therapeutic interventions in AD.
阿尔茨海默病（AD）主要由有毒的淀粉样β蛋白（Aβ）聚集体的形成所驱动，其中Aβ42是疾病病理的关键促成因素。本研究调查了一种新型药物，通过将Aβ42与其G37V变体（Aβ42(G37V)）共组装来减轻Aβ42诱导的毒性，其中37位的甘氨酸被缬氨酸取代。通过硫黄素-T（Th-T）荧光测定、蛋白质印迹分析、原子力显微镜（AFM）/透射电子显微镜（TEM）以及生化测定等方法的结合，我们证明添加Aβ42(G37V)可显著加速Aβ42的聚集速率和聚集量，同时改变所得聚集体的形态。因此，添加Aβ42(G37V)可降低Aβ42聚集体诱导的细胞毒性，细胞活力测定结果的改善证明了这一点。这种效应的可能机制是，添加Aβ42(G37V)可减少活性氧（ROS）的产生和脂质过氧化，而在Aβ42作用下这些通常会升高，这表明其对氧化应激具有保护作用。这些发现表明，Aβ42(G37V)可能是调节Aβ42聚集动力学并降低其神经毒性作用的有前途的候选物，为AD的潜在治疗干预提供了一条新途径。
