A rare ADAM17 variant is associated with familial Alzheimer disease and regulates APP gene expression

Hartl, Daniela and May, Patrick and Gu, Wei and Mayhaus, Manuel and Glaab, Enrico and Reddy, Dheeraj and Bobbili, Paul Antony and Koegelsberger, Sandra and Pichler, Sabrina and Spaniol, Christian and Kurz, Alexander and Morgan, Kevin and Bras, Jose and Guerreiro, Rita and Balling, Rudi and Schneider, Jochen G. and Riemenschneider, Matthias (2018) A rare ADAM17 variant is associated with familial Alzheimer disease and regulates APP gene expression. Molecular Psychiatry . ISSN 1476-5578 (In Press)

[img] PDF - Repository staff only until 11 October 2018. - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (652kB)


The amyloid cascade hypothesis is the prevailing theory on the pathogenesis of Alzheimers’s disease (AD). Functional studies of the amyloidogenic pathway so far were mainly focused on alterations of APP processing, but upregulation of APP expression has recently gained major attention as another contributing factor in AD. Using whole-genome sequencing we identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping of case/control samples identified two additional variant carriers among AD patients. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 α-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, SNV p.R215I carriers show elevated Aß formation. This novel pathway strongly supports a causative association of ADAM17 in the pathogenesis of AD.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Depositing User: Eprints, Support
Date Deposited: 11 Apr 2018 13:38
Last Modified: 11 Apr 2018 13:44
URI: http://eprints.nottingham.ac.uk/id/eprint/51095

Actions (Archive Staff Only)

Edit View Edit View