CLIC1 and IFITM2 expression in brain tissue correlates with cognitive impairment via immune dysregulation in sepsis and Alzheimer's disease.

BACKGROUND

Sepsis, a life-threatening condition driven by dysregulated host responses to infection, is associated with long-term cognitive impairments resembling Alzheimer's disease (AD). However, the molecular mechanisms linking sepsis-induced cognitive dysfunction and AD remain unclear. We hypothesized that shared genetic pathways underlie cognitive deficits in both conditions.

METHODS

Cecal ligation and puncture (CLP) in C57BL/6 J mice modeled sepsis-induced cognitive decline and amyloid pathology. Brain tissue datasets (GSE33000 for AD; GSE135838 for sepsis) were analyzed via Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and functional enrichment. Key genes were validated through ROC analysis, immune infiltration profiling, and in vivo/in vitro experiments.

RESULTS

Sepsis accelerated cognitive decline and AD-like pathology in mice. Bioinformatics identified CLIC1 and IFITM2 as co-diagnostic genes linked to immune dysregulation in both sepsis and AD. Immune infiltration revealed reduced neutrophils/NK cells, M1 macrophage polarization, and naïve-to-memory B cell shifts in sepsis versus AD. CLIC1 and IFITM2 were upregulated in CLP mice and cytokine-stimulated human cerebral endothelial cells, aligning with bioinformatics predictions.

CONCLUSION

CLIC1 and IFITM2, pivotal in immune cell activation, emerged as shared biomarkers of sepsis-related cognitive impairment and AD. These findings highlight immune-driven molecular intersections in cognitive deficits, offering novel targets for mechanistic research and therapeutic development.