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:
CreatorsEmailORCIDORCID Put Code
Rehker, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodhe, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nesbitt, Ryan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boyle, Evan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, Beth K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lord, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karaca, IlkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naj, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jessen, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helisalmi, SeppoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soininen, HilkkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hiltunen, MikkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Scherer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrer, Lindsay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haines, Jonathan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pericak-Vance, Margaret A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raskind, Wendy H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruchaga, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellenberg, Gerard D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joseph, BertrandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brkanac, ZoranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
AMYLOID PRECURSOR PROTEIN; NON-APOPTOTIC ROLES; CELL-DEATH; NEURONAL APOPTOSIS; MISSENSE MUTATIONS; TREM2 DEFICIENCY; CODING VARIANTS; MOUSE MODELS; BETA; GENEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21449

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item