Year: 2026
Type: preprint
Abstract: Glucagon-like peptide-1 (GLP-1) is best known as a receptor agonist, yet its peptide-level behavior in protein-rich environments remains poorly defined. Here, a GLP-1-directed photoaffinity probe recovered a predefined Aβ42 spike-in from cell lysates, while endogenous actin and α-synuclein were detected in the recovered fractions. This observation motivated chemically defined assembly studies with the actinlinked β-thymosin reference TMSB4Y. Thioflavin T (ThT) kinetics and endpoint electron microscopy (EM) revealed no single pro- or antiassembly response. GLP-1 advanced the ThT-positive transition of Tyr10-unmodified Aβ42, whereas TMSB4Y attenuated it. Phosphorylation or nitration at Tyr10 changed both the direction and timing of these effects, and GLP-1 added after assembly had begun redirected established trajectories in a Tyr10-modification-dependent manner. Ser18 O-GlcNAcylation of GLP-1 provided an orthogonal perturbation, suppressing the Tyr10-unmodified response while enhancing the nitrated trajectory and delaying the phosphorylated one. Together, capture in a complex protein background and assembly in defined mixtures identify GLP-1 as a context-sensitive modulator of Aβ42 assembly rather than a fixed promoter or inhibitor.
Source: ChemRxiv
Author: Pritam Ghosh
Institution: Humboldt-Universität zu Berlin
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221148068