Orthogonal Ionic Liquid-based Extraction Strategy Enables Amyloid-Specific Profiling of the Aggregate Proteome

ABSTRACT: Amyloid deposits are key pathological features of neurodegenerative diseases, yet their structural heterogeneity coupled with a stable β-sheet fibrillar architecture makes them extremely insoluble and difficult to isolate. Through systematic screening and molecular dynamics simulations, we identified the ionic liquid TMGBF4, which disrupts β-sheet hydrogen bonds to specifically and preferentially solubilize amyloid aggregates. By harnessing C12ImCl-mediated hydrophobic interactions, we developed an orthogonal ionic-liquid extraction strategy (Orth-iEA) for highly selective amyloid fibril isolation. Applied to an Alzheimer’s disease mouse model, Orth-iEA enabled in-depth amyloid proteome profiling, enhanced detection of low-abundance proteins, and revealed mitochondrial involvement in amyloid pathology. This methodology delivers a versatile chemical strategy advances amyloid research beyond compositional profiling, enabling high-fidelity isolation and deep proteomic analysis of aggregation-driven pathology.

ORGANISM(S): Mus Musculus

SUBMITTER: Lihua Zhang  

PROVIDER: PXD069689 | iProX | Fri Oct 17 00:00:00 BST 2025

REPOSITORIES: iProX