Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over

Although the association between cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and neurocognitive disorders is recognized, the underlying mechanisms remain unclear. To date, no studies have linked alterations in lung and brain barrier permeability to the “spill-over” of inflammatory factors in CS induced COPD-related neurocognitive disorders (COPD-NCDs). Using GWAS data, a two-sample Mendelian randomization (MR) analysis was conducted to explore the genetic associations between COPD and neurocognitive disorders (dementia, Alzheimer’s disease, etc.). A BALB/c female mouse model with CS exposure (9 cigarettes/day × 24 weeks) was established. Cognitive functions were evaluated using open field tests, novel object recognition tests, and Morris water maze tests. Histopathological changes were observed by HE and Masson staining. Cellular and molecular profiles in brain tissues were analyzed by single-cell RNA sequencing. Levels of inflammatory factors were detected by ELISA. Barrier permeability changes in the lungs and brain were assessed by using Evans Blue staining. Tight junction proteins in lung and brain tissues were measured by immunofluorescence and Western blotting. MR analysis revealed causal associations between COPD and Alzheimer’s disease, dementia, depression, anxiety, and Parkinson’s disease. CS-exposed mice exhibited COPD phenotypes (emphysema, reduced lung function) and cognitive impairments (memory deficits, anxiety-like behaviors). Activation of microglia/astrocytes and decreased neuronal/synaptic marker expression were observed in the hippocampus. Increased leakage of Evans blue staining in the lungs and brain, along with downregulated expression of tight junction proteins (Occludin, Claudin1, ZO-1), indicated increased blood-brain barrier (BBB) permeability. Elevated levels of inflammatory factors (IL-1β, IL-6, TNF-α) were detected in lung tissues, brain tissues and serum. CS exposure disrupts lung barrier function, leading to the “spill-over” of inflammatory factors to the brain via the lung-brain axis. This increases BBB permeability, triggering neuroinflammation, impairing hippocampal neuronal and synaptic function, and ultimately causing neurocognitive disorders. This study elucidates a novel mechanism of COPD-NCDs, which may provide new targets for the treatment of COPD-NCDs.