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

Overview

1. Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
2. Department of Pharmacy, The 940th Hospital of Joint Logistics Support force of People’s Liberation Army (PLA), Lanzhou, Gansu, China

Abstract

Introduction: 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.

Methods: Male C57BL/6 J mice were allocated into two groups: control group and hypobaric hypoxia (HH) group. The cognitive function was assessed using novel object recognition test and Morris water maze test. The histological analysis was performed using Hematoxylin-Eosin (HE) staining and Nissl staining. Evans blue (EB) assay was performed to evaluate the integrity of the blood-brain barrier (BBB). The gene levels in hippocampal tissue were assessed 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.

Results: HH exposure led to pathological changes in hippocampal tissue, accompanied by increased oxidative stress, inflammatory response, and BBB disruption, and then induced impaired cognitive function in mice. In the HACD mice, 178 DEGs (70 upregulated and 108 downregulated genes) were found, in comparison to the control, and 8 hub genes were identified. 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 four hub genes (Vwf, Vegfa, Kdr, Spp1) closely related to the 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. Downstream analysis revealed significantly decreased expression of antioxidant proteins Nrf2 and HO-1, accompanied by increased phosphorylation of NF-κB, indicating enhanced neuroinflammation and impaired antioxidant defenses.

Conclusions: Our results reveal a significant association between PI3K/AKT signaling pathway inhibition and HACD and offer potential therapeutic targets for developing novel treatment strategies for HACD.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE290548, at NCBI GEO; found in “Data availability statement”

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: RNA-Seq data can be found online at: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE290548.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, pages, dates, 5 authors, 5 keywords, 1 funder, 56 references.

Cite

This paper

Xin, Y., Yang, C., Wang, G., Ma, H., & Jing, L. (2026). Transcriptomic analysis and experimental verification reveal the involvement of PI3K/AKT signaling pathway in high-altitude cognitive dysfunction. Frontiers in physiology, 17, 1781613. https://doi.org/10.3389/fphys.2026.1781613

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