Genetic interactions found between calcium channel genes modulate amyloid load measured by positron emission tomography

Abstract

Late-onset Alzheimer’s disease (LOAD) is known to have a complex, oligogenic etiology, with considerable genetic heterogeneity. We investigated the influence of genetic interactions between genes in the Alzheimer’s disease (AD) pathway on amyloid-beta (Aβ) deposition as measured by PiB or AV-45 ligand positron emission tomography (PET) to aid in understanding LOAD’s genetic etiology. Subsets of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts were used for discovery and for two independent validation analyses. A significant interaction between RYR3 and CACNA1C was confirmed in all three of the independent ADNI datasets. Both genes encode calcium channels expressed in the brain. The results shown here support previous animal studies implicating interactions between these calcium channels in amyloidigenesis and suggest that the pathological cascade of this disease may be modified by interactions in the amyloid-calcium axis. Future work focusing on the mechanisms of such relationships may inform targets for clinical intervention.

Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: A review on experimental progress and computational modeling

“…Pierrot et al suggested increased Ca 2+ liberation from the ER alone may not be enough to trigger intraneuronal Ab production, which requires influx of extracellular Ca 2+ and a sustained increase in cytosolic Ca 2+ concentration (Pierrot et al, 2004). This is consistent with results from a recent study, which investigated the interactions between genes of different Ca 2+ channels in the AD pathway from a genetic perspective using an online database (Koran et al, 2014). In their study, genes RYR3 and CACNA1C have shown to interact significantly with each other, suggesting this interaction may result in Ca 2+ dysregulation, leading to enhanced Ab production and deposition.…”

Vitamin D cell signalling in health and disease

“…5) [127]. Such L type Ca 2þ channel activation of Ca 2þ release from RYRs also plays a significant role in AD pathology [132,175]. In addition, ROS inhibits the activity of the NMDARs that are responsible for the pulses of Ca 2þ that initiate memory formation [195,196].…”

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

“…These efforts have led to the confirmation of several AD risk genes and the identification of novel risk loci, either alone [29] or as part of larger data sets provided by such consortia as Enhancing Neuro Imaging Genetics Through Meta Analysis or Cohorts for Heart and Aging Research in Genomic Epidemiology [30,31]. Further refinements to GWAS have included pathway and network analyses [32][33][34], the use of proteomics [35], and whole exome data [36], and copy number variant analysis. The latter refinement, in particular, has identified novel candidate AD susceptibility loci [37][38][39].…”