Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach

Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions.
The SL pathway has been shown to be affected in several brain-related disorders, including
Alzheimer’s disease (AD). Recent evidence suggests that epigenetic dysregulation plays an
important role in the pathogenesis of AD as well. Here, we use an integrative approach to
better understand the relationship between epigenetic and transcriptomic processes in
regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of
252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32
healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD
patients. Additionally, methylomic analysis of the same subjects revealed parallel
hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD.
Subsequent gene regulatory network-based analysis identified three candidate genes, i.e.
SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression
program from a diseased towards a healthy state. Together, this epigenomic and
transcriptomic approach highlights the importance of SL-related genes in AD, and may provide
novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways
in AD.