{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:40:45Z","timestamp":1792464045723,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,25]]},"group-title":"Neuroscience","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services","award":["ZIAAG000534"],"award-info":[{"award-number":["ZIAAG000534"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Amyloid \u03b2 (A\u03b2) plaques are a hallmark of Alzheimer\u2019s disease (AD). A human cellular neuronal model that recaptures A\u03b2-induced pathology is critical for advancing AD research. However, comprehensive proteomic profiling of A\u03b2-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\u03b2 (1-42) peptides (A\u03b242A) to improve our understanding of the cellular responses of A\u03b2 aggregates and to establish a human-related platform for AD research. A\u03b242A 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\u03b2-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\u03b242A-iNs system recapitulated molecular signatures observed in AD brain tissue and cerebrospinal fluid. Representative protein changes, including APOE upregulation and its colocalization with A\u03b2 aggregates, were further validated in postmortem human AD brain tissue. Together, these findings manifest that the A\u03b242A-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\u03b2-driven neurodegeneration and for the discovery of therapeutic targets for AD.<\/jats:p>","DOI":"10.64898\/2026.09.20.753014","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:25:11Z","timestamp":1790371511000},"source":"Crossref","is-referenced-by-count":0,"title":["Profiling of Aggregated Amyloid \u03b242-induced Proteomic Alterations in KOLF2.1J Induced Pluripotent Stem Cell-derived Neurons"],"prefix":"10.64898","author":[{"given":"Benjamin","family":"Jin","sequence":"first","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Alzheimer\u2019s and Related Dementias (CARD), 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