{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:21:53Z","timestamp":1792790513558,"version":"4.5.0"},"reference-count":89,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["1RF1AG062479-01"],"award-info":[{"award-number":["1RF1AG062479-01"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In familial Alzheimer\u2019s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eA\u03b2). How PSEN1 E280A ChLNs-eA\u03b2 affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of A\u03b242, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer\u2019s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., A\u03b242, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an \u201camoeboid-like phenotype\u201d), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo\u2122 Red E. coli BioParticles\u2122 phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (\u0394\u03a8m), response to ATP-induced transient intracellular Ca2+ influx, cell polarization (cluster of differentiation 68 (CD68)\/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-\u03b1). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca2+ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-\u03b1. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD.<\/jats:p>","DOI":"10.3390\/ijms26157162","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T15:19:22Z","timestamp":1753370362000},"page":"7162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Induced Microglial-like Cells Derived from Familial and Sporadic Alzheimer\u2019s Disease Peripheral Blood Monocytes Show Abnormal Phagocytosis and Inflammatory Response to PSEN1 E280A Cholinergic-like Neurons"],"prefix":"10.3390","volume":"26","author":[{"given":"Viviana","family":"Soto-Mercado","sequence":"first","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, University of Antioquia, Calle 70#52-21 and Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8824-379X","authenticated-orcid":false,"given":"Miguel","family":"Mendivil-Perez","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Faculty of Nursing, University Research Headquarters, University of Antioquia, Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-0411","authenticated-orcid":false,"given":"Carlos","family":"Velez-Pardo","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, University of Antioquia, Calle 70#52-21 and Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-2386","authenticated-orcid":false,"given":"Marlene","family":"Jimenez-Del-Rio","sequence":"additional","affiliation":[{"name":"Neuroscience Research Group, Institute of Medical Research, Faculty of Medicine, University Research Headquarters, University of Antioquia, Calle 70#52-21 and Calle 62#52-59, Building 1, Laboratory 411\/412, Medellin 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ncl.2017.01.005","article-title":"Early-Onset Alzheimer Disease","volume":"35","author":"Mendez","year":"2017","journal-title":"Neurol. 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