{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:09:03Z","timestamp":1792796943844,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in <jats:italic>PSEN1<\/jats:italic> (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between <jats:italic>PSEN1<\/jats:italic> mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with <jats:italic>PSEN1<\/jats:italic> mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both <jats:italic>PSEN1<\/jats:italic> mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of <jats:italic>PSEN1<\/jats:italic> mutations on neuronal excitability. Additionally, both <jats:italic>PSEN1<\/jats:italic> backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav\/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.<\/jats:p>","DOI":"10.3389\/fncel.2024.1406970","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T04:53:46Z","timestamp":1728449626000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Alzheimer\u2019s disease induced neurons bearing PSEN1 mutations exhibit reduced excitability"],"prefix":"10.3389","volume":"18","author":[{"given":"Simon","family":"Maksour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio K.","family":"Finol-Urdaneta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy J.","family":"Hulme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio e Castro","family":"Cabral-da-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Targa Dias Anastacio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachelle","family":"Balez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calista","family":"Turner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Sanz Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Predrag","family":"Kalajdzic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Lisowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuldip","family":"Sidhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perminder S.","family":"Sachdev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirella","family":"Dottori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lezanne","family":"Ooi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-4939-9412-0_3","article-title":"Generation of neural crest progenitors from human pluripotent stem cells","volume-title":"Neural crest cells","author":"Abu-Bonsrah","year":"2019"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"108615","DOI":"10.1016\/j.celrep.2020.108615","article-title":"Familial Alzheimer\u2019s disease mutations in PSEN1 lead to premature human stem cell neurogenesis","volume":"34","author":"Arber","year":"2021","journal-title":"Cell Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.neulet.2016.12.060","article-title":"Increased susceptibility to A\u03b2 toxicity in neuronal cultures derived from familial Alzheimer\u2019s disease (PSEN1-A246E) induced pluripotent stem cells","volume":"639","author":"Armijo","year":"2017","journal-title":"Neurosci. 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