{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:45:54Z","timestamp":1760150754399,"version":"build-2065373602"},"reference-count":20,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A6A1A03038996","RS-2023-00251396"],"award-info":[{"award-number":["2021R1A6A1A03038996","RS-2023-00251396"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education Korea","award":["2021R1A6A1A03038996","RS-2023-00251396"],"award-info":[{"award-number":["2021R1A6A1A03038996","RS-2023-00251396"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A pathogenic mutation in presenilin-1 (PSEN1), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer\u2019s disease (EOAD). PSEN1 His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid \u00df (A\u03b2) oligomerization tendency with blood. The PSEN1 His214 amino acid position plays a significant role in the gamma\u2013secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-\u03c0 interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-\u03c0 interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid\u2013extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma\u2013secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased A\u03b2 was reflected in the increased A\u03b2 oligomerization tendency and the accumulations of A\u03b2 in the brain from amyloid-PET, leading to EOAD.<\/jats:p>","DOI":"10.3390\/ijms25010116","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T03:36:17Z","timestamp":1703129777000},"page":"116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PSEN1 His214Asn Mutation in a Korean Patient with Familial EOAD and the Importance of Histidine\u2013Tryptophan Interactions in TM-4 Stability"],"prefix":"10.3390","volume":"25","author":[{"given":"Eva","family":"Bagyinszky","sequence":"first","affiliation":[{"name":"Department of Industrial and Environmental Engineering, Graduate School of Environment, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0167-6611","authenticated-orcid":false,"given":"Minju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2756-1786","authenticated-orcid":false,"given":"Young Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam 13120, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9101-5704","authenticated-orcid":false,"given":"SangYun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41583-020-0325-z","article-title":"Cellular senescence and Alzheimer disease: The egg and the chicken scenario","volume":"21","author":"Masliah","year":"2020","journal-title":"Nat. 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