A phage displaying an Aβ-interacting peptide mitigates neurotoxicity and prevents Aβ-driven gene expression changes.

Introduction: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) peptides, which contribute to synaptic dysfunction, neuronal toxicity, and gene expression alterations. In a previous study, we identified a phage displaying a peptide that selectively interacts with Aβ autoantibodies. Methods: Here, we assessed whether this phage also directly interacts with Aβ, as predicted through bioinformatic analyses. We evaluated its functional effects in a neuronal cell line exposed to Aβ and performed transcriptomic profiling by RNA sequencing. Results: We demonstrate that the phage directly interacts with Aβ, consistent with bioinformatic predictions. Functionally, the phage protected the neuronal cell line from Aβ-induced toxicity. RNA sequencing revealed that the phage prevented Aβ-induced alterations in the expression of 1,819 genes, suggesting a role in modulating Aβ-associated metabolic changes. Discussion: These findings highlight the therapeutic potential of phage-displayed peptides in counteracting Aβ toxicity and restoring cellular homeostasis, laying a foundation for future investigations into phage-based interventions for AD.