INTEGRATED TRANSCRIPTOMIC ANALYSIS REVEALS POTENTIAL TRANSPOSABLE ELEMENT ASSOCIATION IN ALZHEIMER’S DISEASE

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by gradual cognitive decline, neuronal dysfunction, extracellar amyloid plaques and intracellular tau tangles. Increasing evidence suggests that transposable elements (TEs), also known as “jumping genes”, become aberrantly activated during aging and can contribute to genomic instability and altered gene regulation in neurodegenerative diseases. However, the relationship between dysregulated TEs and Alzheimer’s disease-associated genes remains insufficiently explored at present. The present study is therefore aimed to investigate the differential expression of TEs in AD and identify TE-associated genes and pathways that are potentially involved in disease pathology through integrated transcriptomic and bioinformatics approach.

Publicly available RNA-sequencing data from post-mortem Alzheimer’s disease and control brain samples were analyzed. Sequence reads were checked for adapter sequences and Phred quality scores, sequences with low Phred score and adapter sequences were timed. The reads were then aligned to the human reference genome, and quantified using the TEtranscripts package. Differential expression analysis was performed using DESeq2 to identify significantly dysregulated TEs. Significant TEs were mapped to overlapping genes using BEDTools, followed by KEGG pathway enrichment, Cytoscape network analysis, and TE–gene correlation analysis.

Differential expression analysis identified significantly upregulated TEs belong to LINE, ERV and DNA transposons family. Genomic mapping analysis identified TE associated genes, some of which were enriched in neuronal related pathways including calcium signaling, cAMP signaling and Cholinergic synapse pathways. Network analysis identified hub genes. Further correlation analysis revealed strong negative association between dysregulated TEs and GSK3B and PRKCA genes, suggesting possible association between TE activity and neuronal pathways in AD.

The results of the study are in line with the growing evidence that TE dysregulation is associated with neurodegenerative diseases. The study also highlights that integrative TE expression profiling along with pathway enrichment, and network biology approach has the potential to unravel the complex and multifaceted molecular mechanisms underlying neurodegeneration.