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However, their structural heterogeneity and extreme insolubility hinder characterization of their molecular composition and deposition mechanisms. Here, an orthogonal ionic liquid\u2010based extraction strategy (Orth\u2010\n                    <jats:italic>i<\/jats:italic>\n                    EA) was developed to selectively enrich amyloid aggregates from complex biological samples. Systematic screening identified tetramethylguanidine tetrafluoroborate (TMGBF\n                    <jats:sub>4<\/jats:sub>\n                    ) as a potent ionic liquid capable of disrupting hydrogen bonds within cross\u2010\u03b2\u2010sheet structures, thereby solubilizing amyloid aggregates. In contrast, 1\u2010dodecyl\u20103\u2010methylimidazolium chloride (C12ImCl) preferentially solubilized non\u2010amyloid proteins through hydrophobic interactions. In combination, these two reagents constitute the orthogonal extraction system, enabling the highly selective enrichment of amyloid aggregates from complex biological samples while remaining compatible with downstream LC\u2010MS\/MS proteomic workflows after mild desalting. Application of Orth\u2010\n                    <jats:italic>i<\/jats:italic>\n                    EA to hippocampal tissue from 12\u2010month\u2010old 3xTg Alzheimer's disease model mice identified numerous amyloid\u2010associated proteins enriched in mitochondrial components, which was further confirmed by immunofluorescence co\u2010localization analysis. Functional and network analyses converged on pathways involving protein transport, mitochondrial translation, intracellular signaling, and apoptosis, revealing previously unrecognized molecular links between amyloid pathology and Alzheimer's disease. Therefore, Orth\u2010\n                    <jats:italic>i<\/jats:italic>\n                    EA provides a versatile chemical platform for selective isolation and molecular profiling of amyloid aggregates.\n                  <\/jats:p>","DOI":"10.1002\/advs.202523685","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:46:32Z","timestamp":1776692792000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Orthogonal Ionic Liquid\u2010Based Extraction Strategy Enables Amyloid\u2010Specific Profiling of Aggregate Proteome"],"prefix":"10.1002","volume":"13","author":[{"given":"Shiying","family":"Zheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medical Proteomics National Chromatographic R. &amp; A. Center Dalian Institute of Chemical Physics Chinese Academy of Sciences  Dalian China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Liu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center for Biology and Chemistry Liaoning Normal University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics National Chromatographic R. &amp; A. 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