The Multimerization State of the Amyloid-β42 Peptide (Aβ42) Governs its Interaction Network with the Extracellular Matrix

The goals of this work were i) to identify the interactions of amyloid-beta (A beta)(42) under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of A beta(42) supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by A beta(42) in the ECM. The ECM and cell surface partners of A beta(42) and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of A beta(42) increased upon its multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among A beta(42) partners decreased upon multimerization. A beta(42) and its supramolecular forms recognized different molecular features on their partners, and the partners of A beta(42) fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. A beta(42) oligomerization triggered interactions with receptors, whereas A beta(42) fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the A beta(42) supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of A beta(42) governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors.