Differential Transcriptome Profiling Unveils Novel Deregulated Gene Signatures Involved in Pathogenesis of Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by a progressive loss of cognitive functions at a higher level than normal aging. Although the apolipoprotein (APOE) gene is a major risk factor in developing AD, other genes have also been reported to be linked with complex phenotypes. Therefore, this genome-wide expression study explored differentially expressed genes as possible novel biomarkers involved in AD. The mRNA expression dataset, GSE28146, containing 15 sample data composed of 7 AD cases from the hippocampus region with age-matched control (n = 8, >80 years), was analyzed. Using “affy” R-package, mRNA expression was calculated, while pathway enrichment analysis was performed to determine related biological processes. Of 58 differentially expressed genes, 44 downregulated and 14 upregulated genes were found to be significantly (p < 0.001) altered. The pathway enrichment analysis revealed two altered genes, i.e., dynein light chain 1 (DYNLL1) and kalirin (KLRN), associated with AD in the elderly population. The majority of genes were associated with retrograde endocannabinoid as well as vascular endothelial growth factors affecting the complex phenotypes. The DYNLL1 and KLRN genes may be involved with AD and Huntington’s disease (HD) phenotypes and represent a common genetic basis of these diseases. However, the hallmark of AD is dementia, while the classic motor sign of HD includes chorea. Our data warrant further investigation to identify the role of these genes in disease pathogenesis.

Keywords: Alzheimer’s disease; differentially expressed genes; microarray analysis; transcriptome analysis.

Figure 1

PC analysis using 58 informative genes. The significantly deregulated genes were considered as the genetic variation among the different AD patients compared to age-matched control individuals. The PC1 is represented by the X- and Y-axes, respectively. AD: Alzheimer’s disease, PC1: First principal component, PC2: Second principal component.

Figure 2

Gene expression for the 58 genes is depicted in the heatmap plot where rows and columns indicate genes and samples, respectively. Upregulated and downregulated genes have been denoted by red and blue color codes. Color intensity specifies the level of up- or downregulated genes.

Figure 3

Classification of DEGs based on their protein class. The PANTHER Protein Class ID is mentioned with the protein class. (A) Pie diagram showing the percentage of genes associated with different protein classes. (B) A list of differentially expressed genes belonging to a specific protein class. DEGs: Differentially expressed genes.

Figure 4

PCA of DEGs in AD. The DEGs are shown in black colored text, while red colored text represents linker proteins that are fetched from the pathway database to extract curated pathways annotation. The “→” indicates activating/catalyzing, while “-|” implies inhibitory activity. Functional interactions and predicted functional interactions have been shown through “-” and “—”, respectively. The network topology/properties are shown as inlet. PCA: Pathway enrichment analysis, DEGs: Differentially expressed genes, AD: Alzheimer’s disease.