γ-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of over 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 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 4 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 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 wild type APH-1B or the APH-1B T27I variant was stably expressed. We then tested the impact of expressing either wild type APH-1B or the APH-1B T27I variant on γ-secretase processing of human APP, the murine Notch derivative mNΔE, and human neuregulin-1 (NRG-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 γ-secretase processing of established substrates compared with cells expressing wild-type APH-1B.© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
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