{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T15:33:12Z","timestamp":1759937592460,"version":"3.37.3"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T00:00:00Z","timestamp":1580256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100007625","name":"Cure Alzheimer's Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007625","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>\u03b3-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of more than 100 membrane-bound substrates. The complex is composed of presenilin (PS1 or PS2), anterior pharynx defect-1 (APH-1), nicastrin (NCT) and PEN-2 and early-onset; autosomal dominant forms of Alzheimer\u2019s disease (AD) are caused by inheritance of mutations of PS. No mutations in genes encoding NCT, or PEN-2 have been identified to date that cause AD. In this regard, a large genetic meta-analysis of four cohorts consisting of more than 600 000 individuals identified a common missense variant, rs117618017 in the APH1B gene that results in a T27I mutation, as a novel genome-wide significant locus. In order to confirm the findings that rs117618017 is associated with risk of AD, we performed a genetic screen from deep whole genome sequencing of the large NIMH family-based Alzheimer\u2019s Disease (AD) dataset. In parallel, we sought to uncover potential molecular mechanism(s) by which APH-1B T27I might be associated with AD by generating stable HEK293 cell lines, wherein endogenous APH-1A and APH-1B expression was silenced and into which either the wild type APH-1B or the APH-1B T27I variant was stably expressed. We then tested the impact of expressing either the wild type APH-1B or the APH-1B T27I variant on \u03b3-secretase processing of human APP, the murine Notch derivative mN\u0394E and human neuregulin-1. We now report that we fail to confirm the association of rs1047552 with AD in our cohort and that cells expressing the APH-1B T27I variant show no discernable impact on the \u03b3-secretase processing of established substrates compared with cells expressing wild-type APH-1B.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa017","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T12:19:07Z","timestamp":1579781947000},"page":"955-966","source":"Crossref","is-referenced-by-count":8,"title":["Negative evidence for a role of APH1B T27I variant in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"29","author":[{"given":"Xulun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Can","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry","family":"Prokopenko","sequence":"first","affiliation":[{"name":"Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingxia","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weinong","family":"Han","sequence":"first","affiliation":[{"name":"Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudolph E","family":"Tanzi","sequence":"first","affiliation":[{"name":"Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangram S","family":"Sisodia","sequence":"first","affiliation":[{"name":"Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,1,29]]},"reference":[{"key":"2020041507453047500_ref1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer's disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. 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