Project Summary: A healthy cerebrovascular system is necessary for the brain to function optimally. Vascular dysfunction can cause vascular cognitive impairment and dementia (VCI/D), a devastating disorder that leads to tremendous economic and social burdens on society. These vascular changes lead to diffuse white matter (WM) injury, which not only cause vascular dementia, but also accelerate other types of dementia, including Alzheimer’s disease. However, our understanding of the mechanisms of vascular abnormality to WM injury on the progression of VCI/D is limited. Using both in vitro and in vivo methods, we have obtained exciting preliminary results suggesting that hypoperfusion-initiated endothelial damage, oxidative stress to neurons and oligodendrocyte precursor cells, and protein overload in the cortex play critical roles to WM injury and cognitive impairments. Activating Nrf2a master transcription factor that controls the expression of cytoprotective enzymesprotects the brain against WM injury and cognitive impairments, whereas suppressing Nrf2 exacerbates WM injury and cognitive impairments. The purpose of this proposal is to further investigate the mechanisms responsible for the cell-specific Nrf2 protection against WT injury and cognitive impairment. The overall hypothesis is that Nrf2 attenuates oxidative stress following cerebral hypoperfusion, thereby decreasing BBB leakage and increasing clearance of neurotoxic proteins, allowing preservation of WM and improved cognitive outcomes. Three specific aims are proposed: Aim 1 tests the hypothesis that Nrf2 activation preserves WM integrity and long-term cognitive functions in experimental VCI/D. Aim 2 tests the hypothesis that VE-Cad is an Nrf2 target gene and that EC-specific Nrf2 contributes to the BBB and WM protections in mice after 2VS. Aim 3 tests the hypothesis that CNPase is an Nrf2 target gene in OPC and that PC-specific OPC Nrf2 contributes to OPC differentiation and WM repairs in mice after 2VS. The investigation of the protective actions of Nrf2 may help to clarify the underlying mechanism of vascular contribution to WM injury and dementia, and develop future therapies that boost endogenous cytoprotection in vascular dementia victims.