Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel.
Department of Chemistry, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel.
ACS Chem Neurosci. 2023 Sep 20;14(18):3385-3397. doi: 10.1021/acschemneuro.3c00208. Epub 2023 Aug 14.
An amyloid precursor protein inhibitor (APPI) and amyloid beta 42 (Aβ42) are both subdomains of the human transmembrane amyloid precursor protein (APP). In the brains of patients with Alzheimer's disease (AD), Aβ42 oligomerizes into aggregates of various sizes, with intermediate, low-molecular-weight Aβ42 oligomers currently being held to be the species responsible for the most neurotoxic effects associated with the disease. Strategies to ameliorate the toxicity of these intermediate Aβ42 oligomeric species include the use of short, Aβ42-interacting peptides that either inhibit the formation of the Aβ42 oligomeric species or promote their conversion to high-molecular-weight aggregates. We therefore designed such an Aβ42-interacting peptide that is based on the β-hairpin amino acid sequence of the APPI, which exhibits high similarity to the β-sheet-like aggregation site of Aβ42. Upon tight binding of this 20-mer cyclic peptide to Aβ42 (in a 1:1 molar ratio), the formation of Aβ42 aggregates was enhanced, and consequently, Aβ42-mediated cell toxicity was ameliorated. We showed that in the presence of the cyclic peptide, interactions of Aβ42 with both plasma and mitochondrial membranes and with phospholipid vesicles that mimic these membranes were inhibited. Specifically, the cyclic peptide inhibited Aβ42-mediated mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. We suggest that the cyclic peptide modulates Aβ42 aggregation by enhancing the formation of large aggregates─as opposed to low-molecular-weight intermediates─and as such has the potential for further development as an AD therapeutic.
淀粉样前体蛋白抑制剂 (APPI) 和淀粉样 β42 (Aβ42) 均为人跨膜淀粉样前体蛋白 (APP) 的亚结构域。在阿尔茨海默病 (AD) 患者的大脑中，Aβ42 寡聚形成各种大小的聚集体，目前认为中间低分子量 Aβ42 寡聚物是与疾病相关的最具神经毒性作用的物质。减轻这些中间 Aβ42 寡聚物毒性的策略包括使用短的、与 Aβ42 相互作用的肽，这些肽要么抑制 Aβ42 寡聚物的形成，要么促进其转化为高分子量聚集体。因此，我们设计了这样一种基于 APPPI 的 β-发夹氨基酸序列的 Aβ42 相互作用肽，该肽与 Aβ42 的 β-片层样聚集位点具有高度相似性。当这种 20 肽环状肽与 Aβ42 紧密结合（摩尔比为 1:1）时，Aβ42 聚集体的形成得到增强，从而减轻了 Aβ42 介导的细胞毒性。我们表明，在环状肽存在的情况下，Aβ42 与血浆和线粒体膜以及模拟这些膜的磷脂囊泡的相互作用被抑制。具体而言，环状肽抑制 Aβ42 介导的线粒体膜去极化，并减少 Aβ42 介导的细胞凋亡和细胞死亡。我们认为，环状肽通过增强大聚集体的形成（而不是低分子量中间产物）来调节 Aβ42 聚集，因此有可能进一步开发为 AD 治疗药物。
