Intermittent hypoxic perconditioning improves cognitive function in a mouse model of vascular cognitive impairment and dementia with comorbidities by recovering cerebral blood flow

Vascular cognitive impairment and dementia is a debilitating neurological disorder caused by chronic cerebral hypoperfusion, for which no effective causative treatments are currently available. Intermittent hypoxia has been shown to enhance cerebral blood flow in mice, but its efficacy in a model of vascular cognitive impairment and dementia remains unclear. In this study, we established a mouse model of vascular cognitive impairment and dementia by bilateral carotid artery stenosis. Intermittent hypoxia was induced before and after this stenosis. We found that intermittent hypoxia increased cerebral blood flow, oxygen saturation, and microcirculation in the prefrontal cortex and hippocampus in the model mice, without causing neurovascular damage. Additionally, intermittent hypoxia significantly improved cognitive function in the mouse model of vascular cognitive impairment and dementia, with perconditioning showing greater efficacy than preconditioning. Improvements in cerebral microcirculation and blood flow were positively correlated with cognitive recovery. Even in a mouse model of vascular cognitive impairment and dementia with comorbidities induced by a high-fat, high-fructose diet, intermittent hypoxic perconditioning demonstrated protective effects on cognitive function. Proteomic analysis indicated that mitochondrial protection is a key mechanism, particularly through upregulating NDUFB8 expression and increasing the activity of mitochondrial complex I. These findings suggest that intermittent hypoxia is a potential non-invasive strategy for the prevention and treatment of vascular cognitive impairment and dementia.