Abstract
Deposition of amyloid proteins and their associated interactome is a hallmark of Alzheimer’s disease (AD) and other amyloidosis diseases, with their composition implying disease etiology. However, precise in-situ micro-dissection of amyloid deposits in AD brain tissue remains a challenge. In this work, we first divert the excited state energy of Thioflavin T from singlet fluorescence to triplet photocatalytic amyloid protein labeling through molecular engineering, while maintain its pan-amyloid binding affinity and selectivity. We further demonstrate that the amyloid labeling is catalyzed via type-I radical-based photosensitization with diverse residue modification sites. In female AD mouse brain tissue without homogenization, Amyloid-ID in-situ captures and profiles amy…
Abstract
Deposition of amyloid proteins and their associated interactome is a hallmark of Alzheimer’s disease (AD) and other amyloidosis diseases, with their composition implying disease etiology. However, precise in-situ micro-dissection of amyloid deposits in AD brain tissue remains a challenge. In this work, we first divert the excited state energy of Thioflavin T from singlet fluorescence to triplet photocatalytic amyloid protein labeling through molecular engineering, while maintain its pan-amyloid binding affinity and selectivity. We further demonstrate that the amyloid labeling is catalyzed via type-I radical-based photosensitization with diverse residue modification sites. In female AD mouse brain tissue without homogenization, Amyloid-ID in-situ captures and profiles amyloid deposits, reliably reporting the often-lost tau biomarker. Finally, we provide comparative amyloidomics resources across 3 commonly used AD mouse models, revealing conjunct mitochondrial entangling pattern within amyloid deposits. Overall, we report a photocatalytic proteomics strategy (namely Amyloid-ID) to profile amyloid deposits directly from AD brain tissue.
Data availability
The data supporting the results in this study are available within the paper and its Supplementary Information. All MS data generated in this study are available at ProteomeXchange Consortium [https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID = PXD058639] with the dataset identifier PXD058639. Source data are provided with this paper.
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Acknowledgements
This work was supported, in part, by funds from National Natural Science Foundation of China (22222410 (Y.L.), 22374148 (Y.L.), 22477102 (X.Z.), 22322411 (Q.Z.)); Liaoning Province Science Foundation for Distinguished Young Scholars (2024JH3/50100009 (Y.L.)); International Partnership Program of Chinese Academy of Sciences for Future Network (028GJHZ2023079FN (Y.L.)); Innovation Program of Science and Research from the DICP, CAS (DICP I202529 (Y.L.), DICP I202458 (W.W.), DICP I202310 (Y.L.)); Dalian Science Foundation for Distinguished Young Scholars (2022RJ04 (Y.L.)).
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Author notes
These authors contributed equally: Huan Feng, Qun Zhao.
Authors and Affiliations
State Key Laboratory of Medical Proteomics, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
Huan Feng, Qun Zhao, Fangliang Guo, Jing Yan, Nan Zhao, Rui Sun, Lihua Zhang & Yu Liu 1.
Zhejiang Key Laboratory of Precise Synthesis of Functional Molecules, Department of Chemistry, Westlake University, Hangzhou, China
Huan Feng, Junbao Ma & Xin Zhang 1.
University of Chinese Academy of Sciences, Beijing, China
Huan Feng & Rui Sun 1.
The Second Hospital of Dalian Medical University, Dalian, China
Fangliang Guo, Jing Yan & Yusong Ge 1.
Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Kaini Shen
Authors
- Huan Feng
- Qun Zhao
- Fangliang Guo
- Jing Yan
- Nan Zhao
- Junbao Ma
- Rui Sun
- Kaini Shen
- Yusong Ge
- Xin Zhang
- Lihua Zhang
- Yu Liu
Contributions
H.F. performed the experiments and drafted the manuscript; Q.Z. performed the experiments and edited the manuscript; F.G. and R. S. performed the protein labeling experiments; J.Y. and Y.G. provided the brain sections of AD mouse models; N.Z. prepared protein samples for MS analysis; K.S. provided proteins used in this work; J.M. and X.Z. tested the probes’ fluorescence lifetime; L.Z. and Y.L. conceptualized this work and edited the manuscript.
Corresponding authors
Correspondence to Lihua Zhang or Yu Liu.
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Cite this article
Feng, H., Zhao, Q., Guo, F. et al. Amyloid-ID: photocatalytic profiling of amyloid deposits in Alzheimer’s disease tissue. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68017-4
Received: 14 April 2025
Accepted: 15 December 2025
Published: 09 January 2026
DOI: https://doi.org/10.1038/s41467-025-68017-4