Department of Chemistry, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
Department of Materials Science, University of Milano-Bicocca, Via R. Cozzi 55, Milan, 20125, Italy.
Adv Healthc Mater. 2023 Dec;12(32):e2301527. doi: 10.1002/adhm.202301527. Epub 2023 Nov 3.
Effective and accessible treatments for Alzheimer's disease (AD) are urgently needed. Soluble Aβ oligomers are identified as neurotoxic species in AD and targeted in antibody-based drug development to mitigate cognitive decline. However, controversy exists concerning their efficacy and safety. In this study, an alternative strategy is proposed to inhibit the formation of Aβ oligomers by selectively oxidizing specific amino acids in the Aβ sequence, thereby preventing its aggregation. Targeted oxidation is achieved using biocompatible and blood-brain barrier-permeable multicomponent nanoscintillators that generate singlet oxygen upon X-ray interaction. Surface-modified scintillators interact selectively with Aβ and, upon X-ray irradiation, inhibit the formation of neurotoxic aggregates both in vitro and in vivo. Feeding transgenic Caenorhabditis elegans expressing human Aβ with the nanoscintillators and subsequent irradiation with soft X-ray reduces Aβ oligomer levels, extends lifespan, and restores memory and behavioral deficits. These findings support the potential of X-ray-based therapy for AD and warrant further development.
治疗阿尔茨海默病（AD）的有效且易于获得的方法亟待开发。可溶的 Aβ 寡聚体被鉴定为 AD 中的神经毒性物质，并成为基于抗体的药物开发的靶点，以减轻认知能力下降。然而，其疗效和安全性仍存在争议。在这项研究中，提出了一种替代策略，通过选择性氧化 Aβ 序列中的特定氨基酸来抑制 Aβ 寡聚体的形成，从而阻止其聚集。靶向氧化是通过使用生物相容性和血脑屏障可渗透的多组分纳米闪烁体来实现的，当与 X 射线相互作用时，纳米闪烁体可产生单线态氧。经过表面修饰的纳米闪烁体能与 Aβ 选择性相互作用，在 X 射线照射下，可在体外和体内抑制神经毒性聚集物的形成。用纳米闪烁体喂养表达人 Aβ 的转基因秀丽隐杆线虫，并随后用软 X 射线照射，可降低 Aβ 寡聚体水平，延长寿命，并恢复记忆和行为缺陷。这些发现支持了基于 X 射线的 AD 治疗的潜力，并需要进一步开发。
