{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:59:23Z","timestamp":1785419963864,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,28]]},"group-title":"Neuroscience","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["101069028"],"award-info":[{"award-number":["101069028"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["003701165704"],"award-info":[{"award-number":["003701165704"]}],"id":[{"id":"https:\/\/ror.org\/00ckakm23","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NIH\/NIA","award":["P30 AG066519"],"award-info":[{"award-number":["P30 AG066519"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>The proteasome is a critical cellular degradative machinery impaired in late-stage Alzheimer\u2019s disease (AD). However, the status and activity of the proteasome in early-stage sporadic AD (sAD) is unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>A cellular model of human early-stage sAD was generated from sAD patient iPSC-derived cortical neurons by dual-SMAD inhibition. The iPSCs, neuroprogenitors, and cortical neurons were validated by the expressions of key markers. The level of total intraneuronal A\u03b2 was measured by ELISA. Composition and native proteolytic activities of the proteasome in control and sAD cortical neurons were measured using complementary fluorogenic probes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Control and sAD patients iPSCs expressed pluripotent markers OCT4, NANOG, and SSEA4 which induced into neuroprogenitors expressing NESTIN and PAX6. The neuroprogenitors terminally differentiated into cortical neurons expressing neuronal markers MAP2 and TUJ1, and cortical layer marker TBR1. The level of intraneuronal A\u03b2 in the sAD cortical neurons was significantly higher compared to control. Control and sAD cortical neurons expressed native 30S, 26S, and 20S proteasome assemblies with the sAD cortical neurons displaying higher 20S assemblies. Increased active 20S assemblies was associated with higher \u03b21, \u03b22, and \u03b25 proteolytic sites activities.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>The significant elevation in the proteolytic activities of the \u03b21, \u03b22, and \u03b25 subunits of 20S proteasome in sAD cortical neurons suggests that this may be a possible compensatory response to elevated intraneuronal A\u03b2.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"734021v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.23.734021","type":"posted-content","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T10:50:19Z","timestamp":1782643819000},"source":"Crossref","is-referenced-by-count":0,"title":["Composition and activity of the proteasome in human iPSC-derived neuronal model of early-stage sporadic Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0336-290X","authenticated-orcid":false,"given":"Aderemi Caleb","family":"Aladeokin","sequence":"first","affiliation":[{"name":"Neuroscience Center, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Jeltsch","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayk","family":"Davtyan","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders, Irvine, CA 92697 USA"},{"name":"Sue and Bill Gross Stem Cell Research Center, Irvine, CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Blurton-Jones","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697 USA"},{"name":"Institute for Memory Impairments and Neurological Disorders, Irvine, CA 92697 USA"},{"name":"Sue and Bill Gross Stem Cell Research Center, Irvine, CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jari","family":"Koistinaho","sequence":"additional","affiliation":[{"name":"Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland"},{"name":"Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026063005101622000_2026.06.23.734021v1.1","unstructured":"ADI - Dementia Statistics. 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