Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons
- 1Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institute
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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BibTeX
@misc{jin2026profiling,
title = {{Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons}},
author = {B. Jin and Z. Li and Y. Hao and I. Kowal and J. Epstein and M. Santiana and C. Weller and M. A. Nalls and D. Tao and S. Fang and P. Narayan and A. B. Singleton and K. V. Keuren-Jensen and L. Ferrucci and M. E. Ward and M. R. Cookson and E. Lara and V. H. Ryan and Y. A. Qi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.753014},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.753014v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Profiling of Aggregated Amyloid β42-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons
AU - B. Jin
AU - Z. Li
AU - Y. Hao
AU - I. Kowal
AU - J. Epstein
AU - M. Santiana
AU - C. Weller
AU - M. A. Nalls
AU - D. Tao
AU - S. Fang
AU - P. Narayan
AU - A. B. Singleton
AU - K. V. Keuren-Jensen
AU - L. Ferrucci
AU - M. E. Ward
AU - M. R. Cookson
AU - E. Lara
AU - V. H. Ryan
AU - Y. A. Qi
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.753014
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.753014v1
AB - 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.
ER -