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.
Caplacizumab: an anti-von Willebrand factor antibody for the treatment of thrombotic thrombocytopenic purpura.
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March 20, 2020
- ACC 2020The American College of Cardiology decided to cancel ACC.20/WCC due to COVID-19, which was scheduled to take place March 28-30 in Chicago. However, ACC.20/WCC Virtual Meeting continues to release cutting edge science and practice changing updates for cardiovascular professionals on demand and free through June 2020.
- Psych Congress 2019The annual Psych Congress, held in San Diego, California, from October 3-6, 2019, brings together members of the entire mental health team, including psychiatrists, physician assistants, nurse practitioners, psychologists, and primary care physicians, with experts in mental health to improve patient outcomes through education.