395 Vascular Cognitive Impairment: Novel Endothelial Mechanisms and the Impact of Dietary PUFAs

OBJECTIVES/GOALS: Vascular cognitive impairment (VCI) is the leading cause of dementia behind Alzheimers Disease (AD) and is often the result of brain hypoxia. Diets rich in polyunsaturated fatty acids (PUFAs) can lower cognitive decline and AD incidence in human patients. Therefore, our goal is to determine the mechanisms that PUFAs influence in a mouse model of VCI. METHODS/STUDY POPULATION: We hypothesize that hypoxia promotes endothelial P-tau accumulation and vasotrophic uncoupling, impairing endothelial integrity. Additionally, we believe that a preventative PUFA-enriched diet blocks this uncoupling and subsequently prevents/delays neurovascular dysfunction and cognitive decline. Male and female mice will be administered a control or novel PUFA-enriched dietary intervention 1 month prior to hypoxic injury using the bilateral carotid artery stenosis model. Mice will continue their diet and be assessed for cerebral blood flow, cognitive function, and motor function at 1- & 3-month time points. Following euthanasia, tissue samples from deep cortical regions and microvasculature will be examined for endothelial- & neuronal-specific P-tau accumulation, inflammation, and cell death. RESULTS/ANTICIPATED RESULTS: Preliminary data in our lab indicates that hypoxia leads to a two-fold increase in endothelial P-tau accumulation and lowered mature BDNF (mBDNF) in brain microvascular endothelial cells (BMECs) compared to controls. Further, BMECs cultured in media with the PUFA docasahexaenoic acid (DHA) had lowered P-tau and increased mBDNF after hypoxia compared to controls. Based on this data and past research, we anticipate that mice on the PUFA-enriched diet will have enhanced cognitive and motor function alongside improved cerebral blood flow compared to controls. Also, we expect that mice on our PUFA-enriched diet will have lowered tau pathology, cell death, and neuroinflammation alongside increased blood brain barrier integrity and altered fatty acid composition in brain and vascular tissue samples. DISCUSSION/SIGNIFICANCE: An AHA Presidential Advisory identified cognitive function as modifiable through the management of cardiovascular risk factors, like diet. However, the mechanisms underlying the benefits of PUFA-enriched diets are unknown. Successful completion of these studies will provide insight into the vaso-neuronal protective effects of PUFAs in VCI.