Transcriptomic analysis and experimental verification reveal the involvement of PI3K/AKT signaling pathway in high-altitude cognitive dysfunction

Cognitive impairment is a common symptom for these people entering high altitude. Unfortunately, the potential molecular mechanisms are not totally clear. This study aimed to identify the genes and signaling pathways associated with high-altitude cognitive dysfunction (HACD) in mice. The cognitive function was accessed using novel object recognition test and Morris water maze test. The histological analysis was performed using Hematoxylin-Eosin (HE) staining and Nissl staining. Hippocampus tissue was collected, and the gene levels were accessed via RNA-Seq technique. Differentially expressed genes (DEGs) were identified using the DESeq2 R package, followed by functional and pathway enrichment analyses. The protein-protein interaction (PPI) network was established for screening hub genes, which were subsequently validated by qRT-PCR. The related proteins were detected by Western blot. HH exposure led to pathological changes in hippocampal tissue, accompanied by increased oxidative stress and inflammatory response and then induced impaired cognitive function in mice. In the HACD mice, 695 DEGs (265 upregulated and 430 downregulated genes) were found, in comparison to the control. GO and KEGG enrichment analysis demonstrated that PI3K/AKT signaling pathway is a significantly enriched pathway, suggesting its potential involvement in the pathogenesis of HACD. Then, we performed validation experiments via qRT-PCR for five DEGs (VWF, VEGFa, ANGPT2, THBS1, SPP1) closely related to PI3K/AKT signaling pathway, and the results aligned with the RNA-seq data. Furthermore, Western blot analysis indicated that the PI3K/AKT pathway was substantially inhibited following HH exposure. Our results provide further understanding of the role of the PI3K/AKT signaling pathway in the development of HACD and offer potential therapeutic targets for developing novel treatment strategies for HACD.