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2016 Grants - Hsu
The Role of Inflammation on Endothelial LRP1
Heng-Wei Hsu, Ph.D.
University of California, Irvine
2016 Alzheimer’s Association Research Fellowship (AARF)
How does inflammation reduce the clearance of beta-amyloid from the brain?
Blood vessels of the brain are lined with a thin layer of cells called endothelial cells. Endothelial cells perform many important functions including controlling which molecules from the blood can enter the brain, and helping to remove waste products from the brain by circulating them out through the blood. In Alzheimer’s disease, impaired function of endothelial cells may prevent the brain from clearing the abnormal build-up of beta-amyloid. Beta-amyloid is a protein fragment that forms “plaques” — a hallmark of Alzheimer’s disease.
Recent studies suggest that the protein LRP1 (low-density lipoprotein receptor-related protein 1), which is found on the surface of endothelial cells, may be important for the removal of beta-amyloid from the brain. The loss of LRP1 has been shown in both Alzheimer’s-like mice and in the brain tissue of people who had Alzheimer’s disease, but the mechanisms that drive these changes are not yet known.
Heng-Wei Hsu, Ph.D. and colleagues will examine the factors that may lead to the loss LRP1 in Alzheimer’s disease. In initial studies, the researchers found evidence that brain inflammation, another characteristic feature of Alzheimer’s disease, may contribute to the reduction in LRP1 levels. For their current studies they will administer an inflammatory molecule called interleukin-1beta (IL-1β) to endothelial cells growing in laboratory dishes and measures changes in levels of LRP1 over time. They will also determine how IL-1β affects the genes and proteins that control LRP1 activity.
These studies could shed new light on how inflammation may impact endothelial cell function and contribute to beta-amyloid accumulation in the brain. The results of this work could also inform the development of novel therapies to regulate brain inflammation to help slow or halt the Alzheimer’s disease process.