{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T18:39:43Z","timestamp":1768502383828,"version":"3.49.0"},"posted":{"date-parts":[[2023,2,3]]},"group-title":"Neuroscience","reference-count":75,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations\n                  <jats:italic>in situ<\/jats:italic>\n                  . Here we use machine learning on the full information available in fluorescent excitation\/emission spectra of amyloid binding dyes to identify six distinct different conformational strains\n                  <jats:italic>in vitro<\/jats:italic>\n                  , as well as A\u03b2 deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in A\u03b2 and tau deposits from Down syndrome, sporadic and familial Alzheimer\u2019s disease human brain slices. EMBER has\n                  <jats:italic>in situ<\/jats:italic>\n                  identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick\u2019s disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. There is a need to rapidly identify these amyloid conformations\n                    <jats:italic>in situ<\/jats:italic>\n                    . Here we use machine learning on the full information available in fluorescent excitation\/emission spectra of amyloid binding dyes to identify six distinct different conformational strains\n                    <jats:italic>in vitro<\/jats:italic>\n                    , as well as A\u03b2 deposits in different transgenic mouse models. Our imaging method rapidly identifies conformational differences in A\u03b2 and tau deposits from Down syndrome, sporadic and familial Alzheimer\u2019s disease human brain slices. We also identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Pick\u2019s disease. These findings will facilitate the identification of pathogenic protein aggregates to guide research and treatment of protein misfolding diseases.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.02.01.526692","type":"posted-content","created":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T00:30:11Z","timestamp":1675470611000},"source":"Crossref","is-referenced-by-count":0,"title":["EMBER multi-dimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2524-2201","authenticated-orcid":false,"given":"Hyunjun","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-4447","authenticated-orcid":false,"given":"Peng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoffer D.","family":"Caro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Tengeiji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeo","family":"Yamanoi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Condello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023020610350631000_2023.02.01.526692v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.60.080805.142106"},{"key":"2023020610350631000_2023.02.01.526692v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910163107"},{"key":"2023020610350631000_2023.02.01.526692v1.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0048065"},{"key":"2023020610350631000_2023.02.01.526692v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1894"},{"key":"2023020610350631000_2023.02.01.526692v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509313112"},{"key":"2023020610350631000_2023.02.01.526692v1.6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.75.101304.123901"},{"key":"2023020610350631000_2023.02.01.526692v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.2.503"},{"key":"2023020610350631000_2023.02.01.526692v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1906124116"},{"key":"2023020610350631000_2023.02.01.526692v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature23002"},{"key":"2023020610350631000_2023.02.01.526692v1.10","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1126\/science.abm7285","article-title":"Cryo-EM structures of amyloid-\u03b2 42 filaments from human brains","volume":"375","year":"2022","journal-title":"Science"},{"key":"2023020610350631000_2023.02.01.526692v1.11","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/s41586-022-04670-9","article-title":"Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43","volume":"605","year":"2022","journal-title":"Nature"},{"key":"2023020610350631000_2023.02.01.526692v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv006"},{"key":"2023020610350631000_2023.02.01.526692v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.10.029"},{"key":"2023020610350631000_2023.02.01.526692v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv006"},{"key":"2023020610350631000_2023.02.01.526692v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101267"},{"key":"2023020610350631000_2023.02.01.526692v1.16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41593-019-0541-x","article-title":"\u03b1-Synuclein strains target distinct brain regions and cell types","volume":"23","year":"2020","journal-title":"Nat. Neurosei"},{"key":"2023020610350631000_2023.02.01.526692v1.17","first-page":"1511","article-title":"Cell biology. A unifying role for prions in neurodegenerative diseases","volume":"336","year":"2012","journal-title":"Seienee"},{"key":"2023020610350631000_2023.02.01.526692v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3810"},{"key":"2023020610350631000_2023.02.01.526692v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature20814"},{"key":"2023020610350631000_2023.02.01.526692v1.20","doi-asserted-by":"crossref","first-page":"8637","DOI":"10.1073\/pnas.0712179105","article-title":"The fold of alpha-synuclein fibrils","volume":"105","year":"2008","journal-title":"Proe. Natl. Acad. Sci"},{"key":"2023020610350631000_2023.02.01.526692v1.21","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1021\/jacs.1c12056","article-title":"Binding Sites of a Positron Emission Tomography Imaging Agent in Alzheimer\u2019s \u03b2-Amyloid Fibrils Studied Using 19 F Solid-State NMR","volume":"144","year":"2022","journal-title":"J. Am. Chem. Soc"},{"key":"2023020610350631000_2023.02.01.526692v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1503-3"},{"key":"2023020610350631000_2023.02.01.526692v1.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700804104"},{"key":"2023020610350631000_2023.02.01.526692v1.24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.sbi.2020.05.011","article-title":"Cryo-EM structures of tau filaments","volume":"64","year":"2020","journal-title":"Curr. Opin. Struet. Biol"},{"key":"2023020610350631000_2023.02.01.526692v1.25","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1177\/10.3.355","article-title":"On the Binding of Congo red by Amyloid","volume":"10","year":"1962","journal-title":"J. Histoehem. Cytoehem"},{"key":"2023020610350631000_2023.02.01.526692v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1131"},{"key":"2023020610350631000_2023.02.01.526692v1.27","doi-asserted-by":"publisher","DOI":"10.1021\/cb900112v"},{"key":"2023020610350631000_2023.02.01.526692v1.28","doi-asserted-by":"publisher","DOI":"10.1021\/ja9047043"},{"key":"2023020610350631000_2023.02.01.526692v1.29","doi-asserted-by":"publisher","DOI":"10.1021\/jm030026b"},{"key":"2023020610350631000_2023.02.01.526692v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(04)00853-1"},{"key":"2023020610350631000_2023.02.01.526692v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0162-3"},{"key":"2023020610350631000_2023.02.01.526692v1.32","doi-asserted-by":"publisher","DOI":"10.1007\/s11307-013-0667-2"},{"key":"2023020610350631000_2023.02.01.526692v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.07.037"},{"key":"2023020610350631000_2023.02.01.526692v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0454-y"},{"key":"2023020610350631000_2023.02.01.526692v1.35","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41586-020-2043-0","article-title":"Novel tau filament fold in Corticobasal degeneration","volume":"580","year":"2020","journal-title":"Nature"},{"key":"2023020610350631000_2023.02.01.526692v1.36","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41586-021-03911-7","article-title":"Structure-based classification of tauopathies","volume":"598","year":"2021","journal-title":"Nature"},{"key":"2023020610350631000_2023.02.01.526692v1.37","doi-asserted-by":"crossref","unstructured":"Yang, Y. , Shi, Y. , Schweighauser, M. , Zhang, X. , Kotecha, A. , Murzin, A. G. , Garringer, H. J. , Cullinane, P. W. , Saito, Y. , Foroud, T. , Warner, T. T. , Hasegawa, K. , Vidal, R. , Murayama, S. , Revesz, T. , Ghetti, B. , Hasegawa, M. , Lashley, T. , Scheres, S. H. W. , Goedert, M. Structures of \u03b1-synuclein filaments from human brains with Lewy pathology. Nature (2022).","DOI":"10.1038\/s41586-022-05319-3"},{"key":"2023020610350631000_2023.02.01.526692v1.38","doi-asserted-by":"publisher","DOI":"10.4161\/pri.29239"},{"key":"2023020610350631000_2023.02.01.526692v1.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713215114"},{"key":"2023020610350631000_2023.02.01.526692v1.40","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41586-020-1984-7","article-title":"Discriminating \u03b1-synuclein strains in Parkinson\u2019s disease and multiple system atrophy","volume":"578","year":"2020","journal-title":"Nature"},{"key":"2023020610350631000_2023.02.01.526692v1.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714966115"},{"key":"2023020610350631000_2023.02.01.526692v1.42","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s40478-021-01298-0","article-title":"Emergence of distinct and heterogeneous strains of amyloid beta with advanced Alzheimer\u2019s disease pathology in Down syndrome","volume":"9","year":"2021","journal-title":"Acta Neuropathol. Commun"},{"key":"2023020610350631000_2023.02.01.526692v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/0169-7439(87)80084-9"},{"key":"2023020610350631000_2023.02.01.526692v1.44","doi-asserted-by":"crossref","first-page":"861","DOI":"10.21105\/joss.00861","article-title":"UMAP: Uniform Manifold Approximation and Projection","volume":"3","year":"2018","journal-title":"J. Open Source Softw"},{"key":"2023020610350631000_2023.02.01.526692v1.45","doi-asserted-by":"crossref","unstructured":"He, K. , Zhang, X. , Ren, S. , Sun, J. Deep Residual Learning for Image Recognition. Proc. IEEE Comput. Soc. Conf. Comput. Vis. Pattern Recognit. 770\u2013778 (2016).","DOI":"10.1109\/CVPR.2016.90"},{"key":"2023020610350631000_2023.02.01.526692v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.05.003"},{"key":"2023020610350631000_2023.02.01.526692v1.47","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00401-021-02294-3","article-title":"Cryo-EM structures of tau filaments from Alzheimer\u2019s disease with PET ligand APN-1607","volume":"141","year":"2021","journal-title":"Acta Neuropathol"},{"key":"2023020610350631000_2023.02.01.526692v1.48","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1038\/s41467-022-32951-4","article-title":"Structure-based discovery of small molecules that disaggregate Alzheimer\u2019s disease tissue derived tau fibrils in vitro","volume":"13","year":"2022","journal-title":"Nat. Commun"},{"key":"2023020610350631000_2023.02.01.526692v1.49","doi-asserted-by":"crossref","unstructured":"Merz, G. E. , Chalkley, M. J. , Tan, S. , Tse, E. , Lee, J. , Prusiner, S. B. , Paras, N. A. , DeGrado, W. F. , Southworth, D. R. Stacked binding of a small molecule PET tracer to Alzheimer\u2019s tau paired helical filaments. (2022) bioRxiv doi: https:\/\/doi.org\/10.1101\/2022.09.30.510175.","DOI":"10.1101\/2022.09.30.510175"},{"key":"2023020610350631000_2023.02.01.526692v1.50","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/jnc.15557","article-title":"Structural amyloid plaque polymorphism is associated with distinct lipid accumulations revealed by trapped ion mobility mass spectrometry imaging","volume":"160","year":"2022","journal-title":"J. Neurochem"},{"key":"2023020610350631000_2023.02.01.526692v1.51","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00476-x"},{"key":"2023020610350631000_2023.02.01.526692v1.52","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24559"},{"key":"2023020610350631000_2023.02.01.526692v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0132-6"},{"key":"2023020610350631000_2023.02.01.526692v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00245-3"},{"key":"2023020610350631000_2023.02.01.526692v1.55","doi-asserted-by":"crossref","first-page":"e46775","DOI":"10.7554\/eLife.46775","article-title":"Inhibition of synucleinopathic seeding by rationally designed inhibitors","volume":"9","year":"2020","journal-title":"Elife"},{"key":"2023020610350631000_2023.02.01.526692v1.56","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cbpa.2021.06.010","article-title":"Catalytic amyloids: Is misfolding folding?","volume":"64","year":"2021","journal-title":"Curr. Opin. Chem. Biol"},{"key":"2023020610350631000_2023.02.01.526692v1.57","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1914-z"},{"key":"2023020610350631000_2023.02.01.526692v1.58","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1002\/cbic.200700146","article-title":"Pyrene excimer-based dual-emission detection of a oligoaspartate tag-fused protein by using a Zn(II)-DpaTyr probe","volume":"8","year":"2007","journal-title":"Chembiochem"},{"key":"2023020610350631000_2023.02.01.526692v1.59","doi-asserted-by":"crossref","unstructured":"Wu, T. , Yu, J. C. , Suresh, A. , Gale-Day, Z. J. , Alteen, M. G. , Woo, A. S. , Millbern, Z. , Johnson, O. T. , Carroll, E. C. , Partch, C. L. , Fourches, D. , Vinueza, N. R. , Vocadlo, D. J. , Gestwicki, J. E. Conformationally responsive dyes enable protein-adaptive differential scanning fluorimetry. (2022) bioRxiv doi: https:\/\/doi.org\/10.1101\/2023.01.23.525251.","DOI":"10.1101\/2023.01.23.525251"},{"key":"2023020610350631000_2023.02.01.526692v1.60","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b02089"},{"key":"2023020610350631000_2023.02.01.526692v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3575"},{"key":"2023020610350631000_2023.02.01.526692v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2005.02.014"},{"key":"2023020610350631000_2023.02.01.526692v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2006.02.009"},{"key":"2023020610350631000_2023.02.01.526692v1.64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1906839116"},{"key":"2023020610350631000_2023.02.01.526692v1.65","doi-asserted-by":"crossref","first-page":"7839","DOI":"10.1021\/jacs.1c03314","article-title":"Inclusion of the C-Terminal Domain in the \u03b2-Sheet Core of Heparin-Fibrillized Three-Repeat Tau Protein Revealed by Solid-State Nuclear Magnetic Resonance Spectroscopy","volume":"143","year":"2021","journal-title":"J. Am. Chem. Soc"},{"key":"2023020610350631000_2023.02.01.526692v1.66","unstructured":"https:\/\/pypi.org\/project\/opencv-python\/"},{"key":"2023020610350631000_2023.02.01.526692v1.67","doi-asserted-by":"publisher","DOI":"10.1145\/3065386"},{"key":"2023020610350631000_2023.02.01.526692v1.68","first-page":"448","volume-title":"Proceedings of the 32nd International Conference on Machine Learning","volume":"37","year":"2015"},{"key":"2023020610350631000_2023.02.01.526692v1.69","unstructured":"Agara, A. F. Deep Learning using Rectified Linear Units (ReLU) (2019)https:\/\/doi.org\/10.48550\/arXiv.1803.08375"},{"key":"2023020610350631000_2023.02.01.526692v1.70","unstructured":"Bates, S. , Hastie, T. , Tibshirani, R. Cross-validation: what does it estimate and how well does it do it? (2022) https:\/\/arxiv.org\/abs\/2104.00673"},{"key":"2023020610350631000_2023.02.01.526692v1.71","unstructured":"Kingma, D. P. , Ba, J. Adam: A Method for Stochastic Optimization. (2017) https:\/\/arxiv.org\/abs\/1412.6980"},{"key":"2023020610350631000_2023.02.01.526692v1.72","unstructured":"Committee for the Update of the Guide for the Care and Use of Laboratory Animals IfLAR; Division of Earth and Life Sciences; National Research Council of the National Academies (2011) Guide for the Care and Use of Laboratory Animals (The National Academies Press, Washington, DC), 8th Ed."},{"key":"2023020610350631000_2023.02.01.526692v1.73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.24.13287"},{"key":"2023020610350631000_2023.02.01.526692v1.74","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1202-06.2006"},{"key":"2023020610350631000_2023.02.01.526692v1.75","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jneumeth.2013.08.018","article-title":"A multispectral LED array for the reduction of background autofluorescence in brain tissue","volume":"220","year":"2013","journal-title":"J. Neurosci. Methods"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.02.01.526692","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:13:36Z","timestamp":1768450416000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.02.01.526692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":75,"URL":"https:\/\/doi.org\/10.1101\/2023.02.01.526692","relation":{},"subject":[],"published":{"date-parts":[[2023,2,3]]},"subtype":"preprint"}}