Effect of ferroptosis on chronic cerebral hypoperfusion in vascular dementia

Vascular dementia (VaD) is the second most prevalent type of dementia after Alzheimer's disease and is caused by impaired nerve cell function resulting from cerebrovascular disease and vascular risk factors. Chronic cerebral hypoperfusion (CCH) is a common pathological and physiological state that may result from cerebral ischemia and hypoxia, causing widespread diffuse lesions in the brain parenchyma which leads to progressive nerve damage. Transferrin (TF) and transferrin receptor 1 (TfR1), two proteins involved in iron uptake, were upregulated by CCH, whereas ferroprotein (FPN), a protein involved in iron efflux, was downregulated. This process may involve various mechanisms including tau and iron regulatory proteins (IRP). CCH can also exacerbate lipid peroxidation caused by an iron imbalance by inhibiting glutathione peroxidase 4 (Gpx4) synthesis and some Gpx4 independent pathways through cystine/glutamate transporters (system Xc^-), ultimately leading to ferroptosis in nerve cells and accelerating the progression of VaD.