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

Authors

Benjamin Jin, Ziyi Li, Ying Hao, Isabelle Kowal, Jacob Epstein, Marianita Santiana, Cory Weller, Mike A Nalls, Dingying Tao, Shengyun Fang, Priyanka Narayan, Andrew B Singleton, Kendall Van Keuren-Jensen, Luigi Ferrucci, Michael E Ward, Mark R Cookson, Erika Lara, Veronica H Ryan, Yue Andy Qi

Published in

bioRxiv : the preprint server for biology. Sep 25, 2026. Epub Sep 25, 2026.

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.

PMID:
42818224
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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