Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models

• 成果类型: Article
• 署名作者: Zhu, Biyue; Liu, Zhenhua; Van, Richard; Wang, Huizhe; Kuang, Shi; Jia, Yuntao; Leon, Erick Calderon; Yang, Fan; Zhang, Jing; Yang, Jun; Hong, Howard; Lobo, Fleur; Yu, Astra; Wang, Johnson; Tanzi, Rudolph E.; Zhang, Can; Mao, Xiaobo; Shao, Yihan; Ran, Chongzhao
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Chongqing Medical University; Central South University; University of Oklahoma System; University of Oklahoma - Norman; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Johns Hopkins University; Johns Hopkins Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2513311123
• 发表日期: 2026-01-13
• 页码: 2513311123
• 关键词: chemiluminescence probe; chemiluminescence imaging; fluorescent probe; biosensors; in vivo bioimaging; alpha-synuclein; BETA-SHEET; CYCLIC AMPLIFICATION; diseases; regions; DESIGN; prions; probes

摘要

Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of alpha-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of alpha-synuclein from A beta. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.