Facultade de Ciencias, Departamento de Química Física, Campus Terra, Universidade de Santiago de Compostela, 27002, Lugo, Spain; Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Facultade de Química, Departamento de Química Física, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Facultade de Ciencias, Departamento de Química Física, Campus Terra, Universidade de Santiago de Compostela, 27002, Lugo, Spain.
Arch Biochem Biophys. 2024 Nov;761:110179. doi: 10.1016/j.abb.2024.110179. Epub 2024 Oct 10.
Amyloid-beta (Aβ) aggregation is a critical factor in the pathogenesis of Alzheimer's disease, with distinct aggregation behaviours observed between its isoforms Amyloid-β 1-40 (Aβ40) and 1-42 (Aβ42). In this study, we investigated the aggregation properties of Aβ40 using fluorescence correlation spectroscopy (FCS) and detailed data analysis. Our results reveal that Aβ40 undergoes a two-step cooperative aggregation process. The first step, characterized by a critical aggregation concentration (cac) of 0.5 ± 0.3 μM, results in the formation of metastable oligomers of 5-25 monomers and stable oligomers of 50-100 monomers, with less than 10 % of the total amyloid aggregated. The second step, with a cac of 19 ± 2 μM, leads to the formation of much larger aggregates, consistent with protofibrils, and approximately 50 % aggregated amyloid. Notably, the cac for Aβ40 is significantly higher, and the fraction of aggregated amyloid is much lower compared to Aβ42, indicating a lower propensity for aggregation. Additionally, our findings suggest that Aβ40 early oligomers are reversible upon dilution, albeit with a kinetic barrier to disaggregation. These insights into the aggregation mechanisms of Aβ40 enhance our understanding of its role in Alzheimer's disease and may inform therapeutic strategies targeting amyloid aggregation.
淀粉样蛋白-β（Aβ）聚集是阿尔茨海默病发病机制的关键因素，其异构体 Aβ1-40（Aβ40）和 1-42（Aβ42）表现出明显不同的聚集行为。在这项研究中，我们使用荧光相关光谱（FCS）和详细数据分析研究了 Aβ40 的聚集特性。我们的结果表明，Aβ40 经历了两步协同聚集过程。第一步，以 0.5±0.3 μM 的临界聚集浓度（cac）为特征，导致 5-25 个单体的亚稳态寡聚物和 50-100 个单体的稳定寡聚物形成，总淀粉样蛋白中只有不到 10%聚集。第二步，cac 为 19±2 μM，导致形成更大的聚合体，与原纤维一致，大约 50%的淀粉样蛋白聚集。值得注意的是，与 Aβ42 相比，Aβ40 的 cac 显著更高，且聚集的淀粉样蛋白分数要低得多，表明其聚集倾向较低。此外，我们的发现表明，Aβ40 早期寡聚物在稀释时是可逆的，尽管解聚集存在动力学障碍。这些对 Aβ40 聚集机制的深入了解，增强了我们对其在阿尔茨海默病中作用的认识，并可能为针对淀粉样蛋白聚集的治疗策略提供信息。
