Vascular cognitive impairment and dementia (VCID) is a major heterogeneous brain disease caused by multiple factors, and it is the second most common type of dementia in the world. It is caused by long-term chronic low perfusion in the whole brain or local brain area, and it eventually develops into severe cognitive dysfunction syndrome. Because of the disease’s ambiguous classification and diagnostic criteria, there is no clear treatment strategy for VCID, and the association between cerebrovascular pathology and cognitive impairment is controversial. Neuroinflammation is an immunological cascade reaction mediated by glial cells in the central nervous system where innate immunity resides. Inflammatory reactions could be triggered by various damaging events, including hypoxia, ischemia, and infection. Long-term chronic hypoperfusion-induced ischemia and hypoxia can overactivate neuroinflammation, causing apoptosis, blood–brain barrier damage and other pathological changes, triggering or aggravating the occurrence and development of VCID. In this review, we will explore the mechanisms of neuroinflammation induced by ischemia and hypoxia caused by chronic hypoperfusion and emphasize the important role of neuroinflammation in the development of VCID from the perspective of immune cells, immune mediators and immune signaling pathways, so as to provide valuable ideas for the prevention and treatment of the disease.

Hypoxic stress occurs in various physiological and pathological states, such as aging, disease, or high-altitude exposure, all of which pose a challenge to many organs in the body, necessitating adaptation. However, the exact mechanisms by which hypoxia affects advanced brain function (learning and memory skills in particular) remain unclear. In this study, we investigated the effects of hypoxic stress on hippocampal function. Specifically, we studied the effects of the dysfunction of mitochondrial oxidative phosphorylation using global proteomics. First, we found that hypoxic stress impaired cognitive and motor abilities, whereas it caused no substantial changes in the brain morphology or structure of mice. Second, bioinformatics analysis indicated that hypoxia affected the expression of 516 proteins, of which 71.1% were upregulated and 28.5% were downregulated. We demonstrated that mitochondrial function was altered and manifested as a decrease in NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 expression, accompanied by increased reactive oxygen species generation, resulting in further neuronal injury. These results may provide some new insights into how hypoxic stress alters hippocampal function via the dysfunction of mitochondrial oxidative phosphorylation.