Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons

Jin, B.; Li, Z.; Hao, Y.; Kowal, I.; Epstein, J.; Santiana, M.; Weller, C.; Nalls, M. A.; Tao, D.; Fang, S.; Narayan, P.; Singleton, A. B.; Keuren-Jensen, K. V.; Ferrucci, L.; Ward, M. E.; Cookson, M. R.; Lara, E.; Ryan, V. H.; Qi, Y. A.

doi:10.64898/2026.09.20.753014

bioRxiv · 10.64898/2026.09.20.753014

Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons

Jin, B.·Li, Z.·Hao, Y.·Kowal, I.·Epstein, J.·Santiana, M.·Weller, C.·Nalls, M. A.·Tao, D.·Fang, S.·Narayan, P.·Singleton, A. B.·Keuren-Jensen, K. V.·Ferrucci, L.·Ward, M. E.·Cookson, M. R.·Lara, E.·Ryan, V. H.·Qi, Y. A.

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Abstract

Amyloid[beta]; (A[beta];) plaques are a hallmark of Alzheimer[prime]s disease (AD). A human cellular neuronal model that recaptures A[beta];-induced pathology is critical for advancing AD research. However, comprehensive proteomic profiling of A[beta];-induced cellular model remains elusive. In this study, we investigated the proteomic changes in induced pluripotent stem cell (iPSC)-derived neurons (iNs) exposed to synthetic A[beta]; (1-42) peptides (A[beta];42A) to improve our understanding of the cellular responses of A[beta]; aggregates and to establish a human-related platform for AD research. A[beta];42A formed extracellular aggregates around neuronal soma and neurites, impaired neurite outgrowth, and induced the expression of multiple AD-associated genes, such as APOE, BACE1, ADAM10. To define the molecular landscape of A[beta];-induced neuronal dysfunction, we performed proteomic analyses of whole-cell lysates as well as soma- and neurite-enriched fractions. Proteomic profiling revealed extensive gene alterations in pathways associated with synaptic function, neuronal maintenance, and AD pathogenesis, such as the upregulation of APOE. Importantly, the A[beta];42A-iNs system recapitulated molecular signatures observed in AD brain tissue and cerebrospinal fluid. Representative protein changes, including APOE upregulation and its colocalization with A[beta]; aggregates, were further validated in postmortem human AD brain tissue. Together, these findings manifest that the A[beta];42A-iNs system reproduces multiple cellular and molecular features of AD and exhibits strongly consensus with clinical observations. It provides a valuable platform for investigating A[beta];-driven neurodegeneration and for the discovery of therapeutic targets for AD.

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Jin, B., Li, Z., Hao, Y., Kowal, I., Epstein, J., Santiana, M., Weller, C., Nalls, M. A., Tao, D., Fang, S., Narayan, P., Singleton, A. B., Keuren-Jensen, K. V., Ferrucci, L., Ward, M. E., Cookson, M. R., Lara, E., Ryan, V. H., Qi, Y. A.. 2026-09-25. Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons. https://doi.org/10.64898/2026.09.20.753014

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