Gomes Luiza M F, Bataglioli Janaina C, Jussila Allison J, Smith Jason R, Walsby Charles J, Storr Tim
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Front Chem. 2019 Dec 3;7:838. doi: 10.3389/fchem.2019.00838. eCollection 2019.
Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes () derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the series to bind to Aβ was evaluated by NMR and ESI-MS, and their influence on the Aβ peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aβ peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the complexes modulate Aβ peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aβ aggregation process.
阿尔茨海默病（AD）是最常见的痴呆形式，会导致认知能力丧失，最终导致死亡。该疾病的特征是细胞外淀粉样β（Aβ）肽聚集体的形成以及细胞内tau蛋白的神经原纤维缠结，还有氧化应激。在本研究中，我们研究了一系列源自NAMI - A的钌（III）配合物（），其中咪唑配体已被吡啶衍生物取代，作为AD的潜在治疗药物。通过核磁共振（NMR）和电喷雾电离质谱（ESI - MS）评估了该系列与Aβ结合的能力，并通过电泳凝胶/蛋白质免疫印迹、透射电子显微镜（TEM）、比浊法和Bradford测定法研究了它们对Aβ肽聚集过程的影响。结果表明，这些配合物可能通过组氨酸残基与Aβ肽共价结合。结合后，与单独的肽沉淀相比，这些配合物促进了可溶性高分子量聚集体的形成。此外，TEM分析支持了处理后的无定形和纤维状聚集体形态，而单独的肽仅观察到大型无定形聚集体。总体而言，我们的结果表明这些配合物调节Aβ肽的聚集，然而，吡啶配体大小的变化并没有实质性地改变Aβ的聚集过程。
