Presenter of 1 Presentation
CIRCULAR RNA DETECTION IDENTIFIES CIRCPSEN1 ALTERATIONS IN BRAIN SPECIFIC TO AUTOSOMAL DOMINANT ALZHEIMER DISEASE
Abstract
Aims
We aimed to investigate differences in gene expression of linear and circular transcripts from known Autosomal-dominant Alzheimer disease (ADAD) genes (PSEN1, APP and, PSEN2) in controls, sporadic AD, and ADAD.
Methods
We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPmed pipeline and circular counts using DCC. After stringent QC, we obtained the counts corresponding the ADAD genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups correcting by biological and technical variables. We performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software.
Results
Our results show significant differences in gene counts of circPSEN1 between ADAD cases and controls but not with sporadic AD (ADAD=18, AD=59, Controls=10–p<0.001 log2FC=0.556, Fig.1A). The same trend is found in the replication dataset (ADAD=4, AD=197, Controls=13–p=0.017, log2FC=0.518, Fig.1B). This finding is specific to circular PSEN1; no significant differences were observed for linear PSEN1 . In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 carriers but to ADAD. In-silico functional analyses suggest the involvement of circPSEN1 in the several pathways such as axon guidance (p=3.39×10-07), hippo signaling pathway (p=7.38×10-07), lysine degradation (p=2.48×10-05) or Wnt signaling pathway (p=5.58×10-04) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate the brains from ADAD from the other with an AUC above 0.70.
Conclusions
circPSEN1 show differences that are unique to ADAD that might be related to neuroinflammatory events that lead or are caused by the accumulation of amyloid-beta.