Universität zu Köln

Rehker, Jan, Rodhe, Johanna, Nesbitt, Ryan R., Boyle, Evan A., Martin, Beth K., Lord, Jenny, Karaca, Ilker, Naj, Adam, Jessen, Frank, Helisalmi, Seppo, Soininen, Hilkka, Hiltunen, Mikko, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Scherer, Martin, Farrer, Lindsay A., Haines, Jonathan L., Pericak-Vance, Margaret A., Raskind, Wendy H., Cruchaga, Carlos, Schellenberg, Gerard D., Joseph, Bertrand and Brkanac, Zoran (2017). Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. PLoS One, 12 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

Full text not available from this repository.

Abstract

The accumulation of amyloid beta (A beta) peptide (Amyloid cascade hypothesis), an APP protein cleavage product, is a leading hypothesis in the etiology of Alzheimer's disease (AD). In order to identify additional AD risk genes, we performed targeted sequencing and rare variant burden association study for nine candidate genes involved in the amyloid metabolism in 1886 AD cases and 1700 controls. We identified a significant variant burden association for the gene encoding caspase-8, CASP8 (p = 8.6x10(-5)). For two CASP8 variants, p.K148R and p.I298V, the association remained significant in a combined sample of 10,820 cases and 8,881 controls. For both variants we performed bioinformatics structural, expression and enzymatic activity studies and obtained evidence for loss of function effects. In addition to their role in amyloid processing, caspase-8 and its downstream effector caspase-3 are involved in synaptic plasticity, learning, memory and control of microglia pro-inflammatory activation and associated neurotoxicity, indicating additional mechanisms that might contribute to AD. As caspase inhibition has been proposed as a mechanism for AD treatment, our finding that AD-associated CASP8 variants reduce caspase function calls for caution and is an impetus for further studies on the role of caspases in AD and other neurodegenerative diseases.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rehker, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Rodhe, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Nesbitt, Ryan R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boyle, Evan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, Beth K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lord, Jenny UNSPECIFIED UNSPECIFIED UNSPECIFIED Karaca, Ilker UNSPECIFIED UNSPECIFIED UNSPECIFIED Naj, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED Jessen, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Helisalmi, Seppo UNSPECIFIED UNSPECIFIED UNSPECIFIED Soininen, Hilkka UNSPECIFIED UNSPECIFIED UNSPECIFIED Hiltunen, Mikko UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramirez, Alfredo UNSPECIFIED orcid.org/0000-0003-4991-763X UNSPECIFIED Scherer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Farrer, Lindsay A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Haines, Jonathan L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pericak-Vance, Margaret A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raskind, Wendy H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cruchaga, Carlos UNSPECIFIED UNSPECIFIED UNSPECIFIED Schellenberg, Gerard D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Joseph, Bertrand UNSPECIFIED UNSPECIFIED UNSPECIFIED Brkanac, Zoran UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-214497
DOI:	10.1371/journal.pone.0185777
Journal or Publication Title:	PLoS One
Volume:	12
Number:	10
Date:	2017
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AMYLOID PRECURSOR PROTEIN; NON-APOPTOTIC ROLES; CELL-DEATH; NEURONAL APOPTOSIS; MISSENSE MUTATIONS; TREM2 DEFICIENCY; CODING VARIANTS; MOUSE MODELS; BETA; GENE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21449