Currently, Alzheimer's Disease (AD) is a complex neurodegenerative condition, with limited therapeutic options. Several factors, like Amyloid β (Aβ) aggregation, tau protein hyperphosphorylation, bio-metals dyshomeostasis and oxidative stress contribute to AD pathogenesis. These pathogenic processes might occur in the aqueous phase but also on neuronal membranes. Thus, investigating the connection between Aβ and biomembranes, becomes important for unveiling the molecular mechanism underlying Aβ amyloidosis as a critical event in AD pathology. In this work, the interaction of two peptides, made up with hybrid sequences from Tau protein 9−16 (EVMEDHAG) or 26−33 (QGGYTMHQ) N-terminal domain and Aβ₁₆₋₂₀ (KLVFF) hydrophobic region, with full length Aβ40 or Aβ42 peptides is reported. The studied "chimera" peptides Ac-EVMEDHAGKLVFF-NH₂ (τ₉₋₁₆-KL) and Ac-QGGYTMHQKLVFF-NH₂ (τ₂₆₋₃₃-KL) are endowed with Aβ recognition and metal ion interaction capabilities provided by the tau or Aβ sequences, respectively. These peptides were characterized in previous study along with their metal dependent interaction and amyloidogenesis, either in the presence or absence of metal ion and artificial membranes made up with Total Lipid Brain Extract (TLBE) components, (Sciacca et al., 2020). In the present paper, the ability of the two peptides to inhibit Aβ aggregation is studied using composite experimental conditions including aqueous solution, the presence of metal ions (Cu or Zn), the presence of lipid vesicles mimicking neuronal membranes as well as the co-presence of metals and TLBE artificial membranes. We used Thioflavine-T (ThT) fluorescence or MALDI-TOF spectrometry analysis of Aβ limited proteolysis to respectively monitor the Aβ aggregation kinetic or validation of the Aβ interacting regions. We demonstrate that τ₉₋₁₆-KL and τ₂₆₋₃₃-KL peptides differently affect Aβ aggregation kinetics, with the tau sequence playing a crucial role. The results are discussed in terms of chimera's peptides hydrophobicity and electrostatic driven interactions at the aqueous/membrane interface.

目前，阿尔茨海默病 (AD) 是一种复杂的神经退行性疾病，治疗选择有限。淀粉样蛋白 β (Aβ) 聚集、tau 蛋白过度磷酸化、生物金属稳态失调和氧化应激等几个因素有助于 AD 发病机制。这些致病过程可能发生在水相中，也可能发生在神经元膜上。因此，研究 Aβ 与生物膜之间的联系，对于揭示 Aβ 淀粉样变性作为 AD 病理学中的关键事件的分子机制变得很重要。在这项工作中，两个肽的相互作用，由来自 Tau 蛋白 9-16 (EVMEDHAG) 或 26-33 (QGGYTMHQ) N 端结构域和 Aβ _{16-20 的}杂交序列组成(KLVFF) 疏水区，具有全长 Aβ40 或 Aβ42 肽。研究的“嵌合体”肽 Ac-EVMEDHAGKLVFF-NH ₂ (τ ₉₋₁₆ -KL) 和 Ac-QGGYTMHQKLVFF-NH ₂ (τ ₂₆₋₃₃-KL) 分别具有由 tau 或 Aβ 序列提供的 Aβ 识别和金属离子相互作用能力。在之前的研究中，这些肽连同它们的金属依赖性相互作用和淀粉样蛋白生成，在金属离子存在或不存在的情况下以及由总脂质脑提取物 (TLBE) 成分组成的人工膜中进行了表征（Sciacca 等，2020）。在本文中，使用复合实验条件研究了两种肽抑制 Aβ 聚集的能力，包括水溶液、金属离子（Cu 或 Zn）的存在、模拟神经元膜的脂质囊泡的存在以及共金属和 TLBE 人造膜的存在。我们使用硫黄素-T (ThT) 荧光或 MALDI-TOF 光谱分析 Aβ 限制蛋白水解来分别监测 Aβ 聚集动力学或 Aβ 相互作用区域的验证。我们证明 τ_9-16 -KL 和 τ _26-33 -KL 肽对 Aβ 聚集动力学的影响不同，其中 tau 序列起着至关重要的作用。结果根据嵌合体肽的疏水性和水/膜界面处的静电驱动相互作用进行了讨论。