Receptor modulated assembly and drug induced disassembly of amyloid beta aggregates at asymmetric neuronal model biomembranes
Year: 2025
Type: article
Abstract: Amyloid peptide non-fibrillar oligomers cause neurotoxicity and may contribute to Alzheimer's disease (AD) pathogenesis. Mounting evidence indicates that Aβ 1–42 oligomers disrupt and remodel neuronal membrane , causing neuronal cell death . The involvement of individual neuronal membrane constituents in real-time Aβ 1–42 aggregate assembly is unclear due to complexity of neuronal cell membrane . We used non-Faradaic electrochemical impedance spectroscopy (EIS) to track monomeric Aβ 1–42 peptide binding and aggregation pathways in real-time in asymmetric micropore suspended lipid bilayer membranes with anionic phospholipids and glycosphingolipids . Anionic DOPC :PIP2 pore suspended membrane showed pore-formation within 2 h of incubation, but peptide insertion occurred over 6 h, with an onset time of ∼6–8 h for peptide aggregation at the membrane surface. Among different gangliosides , peptide binding to GM1- and GM3-containing membranes did not result pore development, but receptor mediated peptide aggregation formation caused membrane admittance to decrease within 2 h. In contrast, partial peptide insertion in the membrane surface increases membrane admittance at GD1a and mixed GSL membranes, arresting aggregation. Time-lapsed AFM imaging at asymmetric solid supported lipid bilayers (aSLBs) corroborated EIS findings, capturing pore-formation and receptor mediated peptide assembly routes. Fluorescence lifetime imaging (FLIM) imaging and spatial resolved single-point fluorescence correlation spectroscopy (FCS) at aSLBs revealed membrane-peptide interaction, assembly, and peptide induced membrane reorganization. Treatment with antidepressants fluoxetine and imipramine therapeutics, in synergy, which are cost-effective and capable of crossing the central nervous system (CNS+), resulted in the disassembly of membrane mediated Aβ 1–42 aggregates, but not fibrils. Overall, the data suggests that membrane-mediated aggregate disassembly at the correct timing of AD progression may halt or reverse amyloid assembly through the use of repurposed drugs.
Source: Biophysical Chemistry
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,720
Awards: IPIC_Phase 2, Microcavity Array Supported Lipid Membranes: Highly Versatile Cell Membrane Models in Sickness and in Health., Advanced skills for data analytics in neurological diseases, Shedding light on advanced microscopy; Supramolecular probes for super-resolution microscopy and phototheranostics
OpenAlex ID: W4409107103