Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants

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. SchellenbergBertrand Joseph, Zoran Brkanac

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0185777
JournalPloS one
Volume12
Issue number10
DOIs
StatePublished - Oct 2017

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Rehker, J., Rodhe, J., Nesbitt, R. R., Boyle, E. A., Martin, B. K., Lord, J., Karaca, I., Naj, A., Jessen, F., Helisalmi, S., Soininen, H., Hiltunen, M., Ramirez, A., Scherer, M., Farrer, L. A., Haines, J. L., Pericak-Vance, M. A., Raskind, W. H., Cruchaga, C., ... Brkanac, Z. (2017). Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants. PloS one, 12(10), [e0185777]. https://doi.org/10.1371/journal.pone.0185777