SOX9 Expression Is Increased in Alzheimer's Disease (AD) and Is Associated With Disease Progression and APOE4 Genotype: A Computational Approach

Abstract

Introduction: Alzheimer's disease (AD) is a neurodegenerative disease characterized by depositions of amyloid-β protein leading to neuronal loss. Despite our understanding of the disease several gaps remain, including the role of astrocytes and astrocytic genes in the disease development and progression. Recently, some reports have suggested that SOX9 transcription factor (TF), an important mediator of astrocyte differentiation and maturation, might be linked to AD. Using human AD publicly available dataset, we aimed to analyze SOX9 expression and its relation to disease.

Methodology: The AD gene expression data set was obtained from National Center for Bioinformatics-Gene Expression Omnibus (NCBI-GEO). The GSE48350 consisted of mRNA microarray data from 55 normal controls (173 samples) and 26 AD cases (81 samples) obtained, from four brain regions. The SOX9 expression profile and correlations were analyzed using the R2 Genomics Analysis and Visualization platform.

Results: The SOX9 was significantly upregulated (p<0.001) in AD tissue compared to control cases. The increased expression appeared to be more in the entorhinal cortex (EC) and hippocampus (HC) regions. The SOX9 expression positively correlated with BRAAK stages (p<0.05). Interestingly in AD patients the SOX9 expression was significantly less in APOE3/3 genotypes compared with genotypes containing APOE4 allele. The SOX9 expression negatively correlated with oxidative phosphorylation genes which could suggest a metabolic role for the TF.

Conclusion: From these data we hypothesize that SOX9 acts as a metabolic regulator responding to lipid metabolism disruption associated with APOE4 genotypes. In turn, SOX9 expression could be associated with astrocyte maturation and survival in the disease contributing thus to disease burden and disease progression.

Keywords: alzheimer; apoe; braak; oxidative phosphorylation; sox9.

Figure 1. DEG and SOX9 expression in AD patients vs. control.

A) Volcano plots showing the DEGs as blue dots (DEGs with p-value < 0.05) in AD patients compared to control. B) Log2 expression of SOX9 in AD cases (n=80) and control (n=173). C) Log2 expression of SOX9 in female cases vs. male cases in AD patients and control.  Data represented as median and IQR, the line in the middle of the box represents the median, the bottom line of the box represents the 25th percentile, the upper line of the box represents the 75th percentile, the lower whisker represents the minimum of the 25th percentile, the upper whisker represents the maximum of the 75th percentile. *p value < 0.05, **p < 0.01, ***p < 0.001 DEGs, differentially expressed genes; IQR, interquartile range; AD, Alzheimer's disease

Figure 2. SOX9 expression in brain regions of AD patients.

Log2 expression of SOX9 in four brain regions entorhinal cortex, hippocampus, post-central gyrus, and superior frontal gyrus of control cases (top graph) and AD cases (bottom graph). Data represented as median and IQR. *p < 0.05, **p < 0.01, ***p < 0.001 AD, Alzheimer's disease; IQR, interquartile range

Figure 3. SOX9 expression in BRAAK stages of AD patients.

Log2 expression of SOX9 in six BRAAK stages. Data represented as median and IQR. IQR, interquartile range

Figure 4. SOX9 expression in APOE genotypes of AD patients.

Log2 expression of SOX9 in four APOE genotypes (APOE 2/4, APOE3/3, APOE 3/4, and APOE4/4) of AD patients. Data represented as median and IQR. ***p value < 0.001 relative to APOE3/3