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bioRxiv · 10.1101/2025.01.16.633335

Biflavonoids can potentially inhibit amyloid beta internalization to mitigate its cytotoxic events

Haque, M. A.·Park, I. S.·Hossain, M. S.
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Abstract

Amyloid-{beta}-42 (A{beta}) peptides are key contributors to Alzheimers disease (AD), with recent studies highlighting a strong link between A{beta} toxicity and its internalization into cells. Targeting the internalization of A{beta} using naturally occurring small molecules could represent a promising strategy for developing therapeutic interventions. In this study, we investigated the effects of biflavonoids on inhibiting the internalization of A{beta} and its impact on cellular processes that lead to cell death. Various biochemical techniques were employed to assess the ability of biflavonoids to prevent A{beta}42 uptake and to elucidate the underlying mechanisms of their inhibitory action. Our findings revealed that biflavonoids exert a dose-dependent inhibitory effect on A{beta} toxicity. The cytoprotective effects of biflavonoids were primarily attributed to their ability to block A{beta} internalization, as confirmed through confocal microscopy and validated by western blot analysis. By preventing A{beta} entry into cells, biflavonoids also inhibited A{beta}-induced lamin fragmentation and caspase activation, both of which are critical steps in A{beta}-mediated cytotoxicity. Furthermore, we explored the influence of biflavonoids on the aggregation process of A{beta}, including fibril, oligomer, and {beta}-sheet formation, and found that biflavonoids effectively inhibited these conformational changes. Based on these results, we propose that biflavonoids suppress A{beta} cytotoxicity by blocking its conformational changes and subsequent internalization, thereby highlighting their potential as anti-amyloidogenic therapeutic agents.

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Haque, M. A., Park, I. S., Hossain, M. S.. 2025-01-17. Biflavonoids can potentially inhibit amyloid beta internalization to mitigate its cytotoxic events. https://doi.org/10.1101/2025.01.16.633335

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