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

TitleCaspase-8, association with Alzheimer's Disease and functional analysis of rare variants.
Publication TypeJournal Article
Year of Publication2017
AuthorsRehker J, Rodhe J, Nesbitt RR, Boyle EA, Martin BK, Lord J, Karaca I, Naj A, Jessen F, Helisalmi S, Soininen H, Hiltunen M, Ramirez A, Scherer M, Farrer LA, Haines JL, Pericak-Vance MA, Raskind WH, Cruchaga C, Schellenberg GD, Joseph B, Brkanac Z
JournalPLoS One
Date Published2017
KeywordsAlleles, Alzheimer Disease, Case-Control Studies, Caspase 8, Cell Line, Tumor, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Neurons

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.

Alternate JournalPLoS ONE
PubMed ID28985224
PubMed Central IDPMC5630132
Grant ListU24 AG021886 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States