Aβ deposition is a pathological hallmark of Alzheimer's disease (AD). Besides the full-length amyloid forming peptides (Aβ_1–40 and Aβ_1–42), biochemical analyses of brain deposits have identified a variety of N- and C-terminally truncated Aβ variants in sporadic and familial AD patients. However, their relevance for AD pathogenesis remains largely understudied. We demonstrate that Aβ_4–42 exhibits a high tendency to form β-sheet structures leading to fast self-aggregation and formation of oligomeric assemblies. Atomic force microscopy and electrophysiological studies reveal that Aβ_4–42 forms highly stable ion channels in lipid membranes. These channels that are blocked by monoclonal antibodies specifically recognizing the N-terminus of Aβ_4–42. An Aβ variant with a double truncation at phenylalanine-4 and leucine 34, (Aβ_4–34), exhibits unstable channel formation capability. Taken together the results presented herein highlight the potential benefit of C-terminal proteolytic cleavage and further support an important pathogenic role for N-truncated Aβ species in AD pathophysiology.

Aβ 沉积是阿尔茨海默病 (AD) 的病理标志。除了全长淀粉样蛋白形成肽（Aβ _1-40和 Aβ _1-42）外，脑沉积物的生化分析已在散发性和家族性 AD 患者中鉴定出多种 N 端和 C 端截短的 Aβ 变体。然而，它们与 AD 发病机制的相关性仍未得到充分研究。我们证明 Aβ _4-42表现出形成 β 折叠结构的高度趋势，从而导致快速自聚集和寡聚组装体的形成。原子力显微镜和电生理研究表明 Aβ _4-42在脂质膜中形成高度稳定的离子通道。_{这些通道被特异性识别 Aβ 4-42} N 末端的单克隆抗体阻断。在苯丙氨酸 4 和亮氨酸 34 处具有双截断的 Aβ 变体 (Aβ _4–34 ) 表现出不稳定的通道形成能力。综上所述，本文提出的结果突出了 C 末端蛋白水解切割的潜在益处，并进一步支持了 N-截短的 Aβ 物种在 AD 病理生理学中的重要致病作用。