{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T01:59:58Z","timestamp":1781056798151,"version":"3.54.1"},"reference-count":80,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory impairment and cognitive decline. The APOE4 allele represents one of the most prominent genetic risk factors. In this study, we investigated the impact of APOE4 on the cholinergic neuronal development and on the neuronal inflammatory response to TNF-\u03b1 stimulation. To address this, human induced pluripotent stem cells (hiPSCs) carrying a homozygous APOE4 genotype and an isogenic APOE3 control were differentiated into cholinergic-like induced neurons (iNs) by LHX8 overexpression. APOE4 was associated with accelerated early neuronal differentiation, as reflected by earlier downregulation of the progenitor marker Nestin. However, delayed expression of synaptophysin indicated impaired synaptic maturation. Functionally, APOE3 iNs exhibited a robust but temporally regulated response to TNF-\u03b1, whereas APOE4 iNs were characterized by a delayed yet sustained induction of inflammatory signaling. Moreover, APOE4 iNs displayed an enhanced stress-associated transcriptional response at early differentiation stages. Collectively, these findings suggest that APOE4 influences both neuronal development and the timing and persistence of inflammatory responses, potentially predisposing cholinergic neurons to later dysfunction in AD.<\/jats:p>","DOI":"10.3390\/cells15121057","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:58:12Z","timestamp":1781053092000},"page":"1057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholinergic Differentiation of Human iPSCs Reveals Early APOE4-Driven Dysregulation of Neuronal Markers, Synaptogenesis and Inflammatory Responses"],"prefix":"10.3390","volume":"15","author":[{"given":"Nele Johanne","family":"Czaniera","sequence":"first","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB e.V.), 33611 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Schulten","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Centre NRW, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Pschik","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB e.V.), 33611 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Joneleit","sequence":"additional","affiliation":[{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB e.V.), 33611 Bielefeld, Germany"},{"name":"Department of Molecular Neurobiology, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB e.V.), 33611 Bielefeld, Germany"},{"name":"Department of Molecular Neurobiology, University of Bielefeld, 33615 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kaltschmidt","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany"},{"name":"Forschungsverbund BioMedizin Bielefeld, Ostwestfalen-Lippe (OWL) (FBMB e.V.), 33611 Bielefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1097\/JCMA.0000000000001252","article-title":"A 2025 update on treatment strategies for the Alzheimer\u2019s disease spectrum","volume":"88","author":"Wu","year":"2025","journal-title":"J. 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