Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants.
The accumulation of amyloid beta (Aβ) 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 s...
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doaj-56a02bfc424f407eaf9e982c96880b2c2020-11-25T01:45:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011210e018577710.1371/journal.pone.0185777Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants.Jan RehkerJohanna RodheRyan R NesbittEvan A BoyleBeth K MartinJenny LordIlker KaracaAdam NajFrank JessenSeppo HelisalmiHilkka SoininenMikko HiltunenAlfredo RamirezMartin SchererLindsay A FarrerJonathan L HainesMargaret A Pericak-VanceWendy H RaskindCarlos CruchagaGerard D SchellenbergBertrand JosephZoran BrkanacThe accumulation of amyloid beta (Aβ) 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.http://europepmc.org/articles/PMC5630132?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jan Rehker Johanna Rodhe Ryan R Nesbitt Evan A Boyle Beth K Martin Jenny Lord Ilker Karaca Adam Naj Frank Jessen Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Alfredo Ramirez Martin Scherer Lindsay A Farrer Jonathan L Haines Margaret A Pericak-Vance Wendy H Raskind Carlos Cruchaga Gerard D Schellenberg Bertrand Joseph Zoran Brkanac |
spellingShingle |
Jan Rehker Johanna Rodhe Ryan R Nesbitt Evan A Boyle Beth K Martin Jenny Lord Ilker Karaca Adam Naj Frank Jessen Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Alfredo Ramirez Martin Scherer Lindsay A Farrer Jonathan L Haines Margaret A Pericak-Vance Wendy H Raskind Carlos Cruchaga Gerard D Schellenberg Bertrand Joseph Zoran Brkanac Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. PLoS ONE |
author_facet |
Jan Rehker Johanna Rodhe Ryan R Nesbitt Evan A Boyle Beth K Martin Jenny Lord Ilker Karaca Adam Naj Frank Jessen Seppo Helisalmi Hilkka Soininen Mikko Hiltunen Alfredo Ramirez Martin Scherer Lindsay A Farrer Jonathan L Haines Margaret A Pericak-Vance Wendy H Raskind Carlos Cruchaga Gerard D Schellenberg Bertrand Joseph Zoran Brkanac |
author_sort |
Jan Rehker |
title |
Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. |
title_short |
Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. |
title_full |
Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. |
title_fullStr |
Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. |
title_full_unstemmed |
Caspase-8, association with Alzheimer's Disease and functional analysis of rare variants. |
title_sort |
caspase-8, association with alzheimer's disease and functional analysis of rare variants. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2017-01-01 |
description |
The accumulation of amyloid beta (Aβ) 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. |
url |
http://europepmc.org/articles/PMC5630132?pdf=render |
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