{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:49:46Z","timestamp":1776854986322,"version":"3.51.2"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K16532"],"award-info":[{"award-number":["20K16532"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K08900"],"award-info":[{"award-number":["18K08900"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K08135"],"award-info":[{"award-number":["21K08135"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Seizures are increasingly being recognized as the hallmark of Alzheimer\u2019s disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid \u03b2 (A\u00df) depositions. However, it can also be a cell-autonomous phenomenon causing AD by A\u00df-independent mechanisms. Various studies using animal models have shown that Ca<jats:sup>2+<\/jats:sup> is released from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP<jats:sub>3<\/jats:sub>R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca<jats:sup>2+<\/jats:sup> signaling in neural cells derived from three early-onset AD patients harboring Presenilin-1 variants (<jats:italic>PSEN1<\/jats:italic> p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal A\u00df. We found all <jats:italic>PSEN1<\/jats:italic>-mutant neurons, but not wild-type, caused abnormal Ca<jats:sup>2+<\/jats:sup>-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, an RyR2 inhibitor, and VK-II-86, an analog of carvedilol without the \u03b2-blocking effects, sufficiently eliminated the abnormal Ca<jats:sup>2+<\/jats:sup> bursts. In contrast, Dantrolene, an inhibitor of RyR1 and RyR3, and Xestospongin c, an IP<jats:sub>3<\/jats:sub>R inhibitor, did not attenuate the Ca<jats:sup>2+<\/jats:sup>-bursts. The Western blotting showed that RyR2 expression was not affected by <jats:italic>PSEN1<\/jats:italic> p.A246E, suggesting that the variant may activate the RyR2. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca<jats:sup>2+<\/jats:sup>-transporter genes were decreased in PSEN1<jats:sub>A246E<\/jats:sub> cells compared to the WT neurons. Thus, we propose that aberrant Ca<jats:sup>2+<\/jats:sup> signaling is a key link between human pathogenic <jats:italic>PSEN1<\/jats:italic> variants and cell-intrinsic hyperactivity prior to deposition of abnormal A\u00df, offering prospects for the development of targeted prevention strategies for at-risk individuals.<\/jats:p>","DOI":"10.1371\/journal.pone.0291887","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T19:36:10Z","timestamp":1724355370000},"page":"e0291887","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Carvedilol suppresses ryanodine receptor-dependent Ca2+ bursts in human neurons bearing PSEN1 variants found in early onset Alzheimer\u2019s 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