Identification of Polyphenolic Compounds and Black Tea Extract as Potent Inhibitors of Lipid Membrane Destabilization by Aβ42 Aggregates

Abstract

Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer's disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ₄₂ peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N'-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability to antagonize liposome permeabilization by the Aβ₄₂ oligomers. Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ₄₂ oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD.