Abstract Vascular dementia (VaD) is the second most common cause of dementia overall and the most common in patients < 74 years old. In an aging veteran population, dementia is a critical health care issue that affects 7.3% of veterans ≥ 65 years old1. To prevent or manage VaD, it is critical to understand its early pathophysiology, specifically learning how vascular disease and inflammation, a process that occurs decades before VaD, modulate neuroinflammation and neurodegeneration. We have identified and characterized a novel putative agent for vascular aging, medin, one of the most common human amyloid proteins, found in greater quantities in VaD and Alzheimer's disease (AD) patients, and which can cause endothelial dysfunction, pro-inflammatory activation similar to cardiovascular risk factors (CVRFs), as well as exacerbate hypoxic injury to endothelial cells (ECs). In later stages of vascular disease, atherosclerotic and thromboembolic changes can lead to ischemia and brain tissue hypoxia or stroke, the 5th major cause of mortality. Investigating factors, such as medin, that could potentially exacerbate this injury would lead to new treatment targets. Additionally, we showed that monosialoganglioside-containing nanoliposomes (NLGM1, phospholipid particles <100 nm) protect against hypoxia and oxidative stress-induced endothelial dysfunction and vascular inflammation. Based on these initial discoveries, our overall goal is to investigate how the aging vasculature influences neural inflammation and function and identify novel treatment targets and intervention to mitigate hypoxic injury in VaD. In Aim 1 we will establish mechanisms by which cerebrovascular inflammation modulates neuroinflammation and neurodegeneration. Here we will use 2D cell, novel 3D vascularized brain organ-on-a-chip and isolated ex-vivo collateral cerebral arteries from brain donors with VaD, AD or normal cognition to determine how vascular inflammation induced by medin or CVRFs modulate astrocyte and microglial inflammation and affect neuronal function and viability. In Aim 2, we will establish the role of medin in modulating hypoxic neurovascular unit injury. We will also test whether NLGM1 could protect against hypoxic injury to cellular components of the neurovascular unit using the 3D chip model and perform pilot investigation to test whether NLGM1 can protect mice against hypoxic injury from middle cerebral artery occlusion. Using novel cellular and human tissue models developed by our group, the proposal could impact our fundamental understanding of the early genesis of VaD, identify and characterize medin as a novel treatment target and validate NLGM1 as a novel therapeutic option.