A Phage Displaying Aβ-Interacting Peptide Mitigates Neurotoxicity and Prevents Alterations in Aβ-Driven Changes in Gene Expression

Laura De Plano¹Luigi Chiricosta²Simone D'angiolini²Alessandra Saitta^1,3Alessandra Trainito²Serena Silvestro²Sabrina Conoci¹Salvatore Oddo¹Antonella Caccamo^1*

• ¹University of Messina, Messina, Italy
• ²IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy
• ³Universita degli Studi di Perugia, Perugia, Italy

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. Here, we demonstrate that the same phage directly interacts with Aβ, as predicted through bioinformatic analyses, suggesting a potential innovative therapeutic mechanism. Functionally, we show that this phage protects a neuronal cell line from Aβ-induced toxicity. Furthermore, transcriptomic profiling by RNA sequencing revealed that the phage prevented Aβ-induced alterations in the expression of 1,819 genes, suggesting a potential role in modulating Aβ-associated metabolic changes. 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.