Helical sulfonyl-γ-AApeptides modulating Aβ oligomerization and cytotoxicity by recognizing Aβ helix

• 成果类型: Article
• 署名作者: Liu, Heng; Cui, Yunpeng; Zhao, Xue; Wei, Lulu; Wang, Xudong; Shen, Ning; Odom, Timothy; Li, Xuming; Lawless, William; Karunarathne, Kanchana; Muschol, Martin; Guida, Wayne; Cao, Chuanhai; Ye, Libin; Cai, Jianfeng
• 署名单位: State University System of Florida; University of South Florida; State University System of Florida; University of South Florida; State University System of Florida; University of South Florida; State University System of Florida; University of South Florida
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13747
• DOI: 10.1073/pnas.2311733121
• 发表日期: 2024-02-01
• 关键词: alzheimers-disease; amyloid oligomers; protein aggregation; common mechanism; inhibitors; peptide; a-beta-42; toxicity; forms; antibodies

摘要

In contrast to prevalent strategies which make use of beta-sheet mimetics to block A beta fibrillar growth, in this study, we designed a series of sulfonyl-gamma-AApeptide helices that targeted the crucial alpha-helix domain of A beta 13-26 and stabilized A beta conformation to avoid forming the neurotoxic A beta oligomeric beta-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the A beta oligomerization and fibrillation could be greatly prevented and even reversed in the presence of sulfonyl-gamma-AApeptides in a sequence-specific and dose-dependent manner. The studies based on circular dichroism, Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) spectra unambiguously suggested that the sulfonyl-gamma-AApeptide Ab-6 could bind to the central region of A beta(42) and induce alpha-helix conformation in A beta. Additionally, Electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) was employed to rule out a colloidal mechanism of inhibitor and clearly supported the capability of Ab-6 for inhibiting the formation of A beta aggregated forms. Furthermore, Ab-6 could rescue neuroblastoma cells by eradicating A beta-mediated cytotoxicity even in the presence of pre-formed A beta aggregates. The confocal microscopy demonstrated that Ab-6 could still specifically bind A beta(42) and colocalize into mitochondria in the cellular environment, suggesting the rescue of cell viability might be due to the protection of mitochondrial function otherwise impaired by A beta(42) aggregation. Taken together, our studies indicated that sulfonyl-gamma-AApeptides as helical peptidomimetics could direct A beta into the off-pathway helical secondary structure, thereby preventing the formation of A beta oligomerization, fibrillation and rescuing A beta induced cell cytotoxicity.