The phosphoS655 Alzheimer's Amyloid Precursor Protein (APP) interactome in neuronal differentiation

Almeida, D. L.; da Rocha, J. F.; Cruz, B. C.; Damen, J. M. A.; Altelaar, M.; Osorio, H.; da Cruz e Silva, O. A. B.; Vieira, S. I.

doi:10.64898/2026.03.26.714600

bioRxiv · 10.64898/2026.03.26.714600

The phosphoS655 Alzheimer's Amyloid Precursor Protein (APP) interactome in neuronal differentiation

Almeida, D. L.·da Rocha, J. F.·Cruz, B. C.·Damen, J. M. A.·Altelaar, M.·Osorio, H.·da Cruz e Silva, O. A. B.·Vieira, S. I.

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Abstract

The Alzheimers Amyloid Precursor Protein (APP) has determinant roles in neuronal development and function, both in its full-length conformation and as some of its proteolytic peptides, particularly secreted (s)APPa. Given that APP phosphorylation tightly regulates its trafficking, proteolysis, and protein-protein binding, it consequently affects several APP functions. The S655 residue, located in the basolateral sorting motif YTSI at APP C-terminus has been observed to be phosphorylated in mature full-length APP and its C-terminal fragments. Previously observed to modify APPs protein interactions, resulting in altered endolysosomal trafficking, andincreased half-life and sAPPa generation, phosphoS655 APP has potential to modulate APP-mediated neuronal differentiation. To study the phosphoS655 differential interactome relevant for neuronal differentiation, SH-SY5Y cells expressing Wt or S655 phosphomutants APP-GFP were differentiated at two time points. APP-GFP and their respective interacting partners were immunoprecipitated using GFP-trap, and interactors identified by mass spectrometry. Both dephospho and phosphoS655 interactomes were generally enriched in similar processes, primarily RNA processing and translation, as well as signal transduction, metabolism, and cytoskeleton remodeling. The smaller phosphoS655 interactome contributes for functional specialization via binding to e.g. FUBP3, ELAVL4, ATXN2, Tubulin, INA. Several of these specific binding partners are known to promote neurite outgrowth and likely underlie our experimental observation that phosphoS655 APP promotes neuritogenesis, particularly the formation of longer neuritic extensions. These results are not only important for the body of knowledge on this Alzheimers disease core protein, but may also aid in future therapies against this disease.

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Almeida, D. L., da Rocha, J. F., Cruz, B. C., Damen, J. M. A., Altelaar, M., Osorio, H., da Cruz e Silva, O. A. B., Vieira, S. I.. 2026-03-30. The phosphoS655 Alzheimer's Amyloid Precursor Protein (APP) interactome in neuronal differentiation. https://doi.org/10.64898/2026.03.26.714600

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