Sex‐specific differential gene expression changes in young AD transgenic (APPswe/PS1ΔE9) mice through RNA‐seq

Background Women and men are differently affected in Alzheimer’s disease (AD). However, the factors that contribute to this differential AD epidemiology are not well understood. We, therefore, examined how gene expression changes could work differently in females and males in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD using RNA sequencing (RNA‐seq). Method Total RNA was isolated from EC and HP from 3‐month‐old female and male APP/PS1 transgenic (Tg) and wild type (WT) control mice (n=4). Depletion of ribosomal RNA was performed on the total RNA before cDNA library preparation which was followed by Illumina paired end sequencing. The raw reads were processed to remove reads with low quality and adapters. The reads were then aligned to mouse genome and read counts for all the files were generated from aligned reads using htseq‐count. The counts were then name sorted using samtools and differential gene expression analysis was performed after normalisation using DESeq2 which was followed by pathway analysis using the online application DAVID. Result In both EC and HP in the female and male APP/PS1 mice, APP was found to be upregulated. In the EC, we observed that while 55 genes were upregulated in males, 418 genes were upregulated in female Tg mice as compared to WT with only 10 common genes. Further, while 153 genes showed downregulation in males, 152 genes were downregulated in EC in female Tg mice as compared to WT mice with 10 common genes. In HP, 40 genes were found upregulated in males while only 2 genes in females. The number of downregulated genes in male HP was 46, while it was 3 in female HP. Further, biological pathways such as synapse, cell junction, postsynaptic membrane, calmodulin binding, gap junction, cytoskeleton were perturbed in female Tg mice while in male Tg mice the pathways perturbed were synapse, cell junction, SH3 domain, transcription regulation and neurogenesis. Conclusion Our analysis of transcriptomic data reveals a significant difference between male and female APP/PS1 transgenic mice. Our study therefore, highlights the importance of studying sex‐specific mechanisms of AD pathogenesis.