Grant: CIHR Fellowship

Reductions in blood flow within the brain has been identified as an early event in the development of Alzheimer's disease. It was recently discovered that the smallest blood vessels, capillaries, in the brain of Alzheimer's disease mice were being blocked by an immune cell, and this small blockage was responsible for large reductions in blood flow. Amazingly, when the immune cells were prevented from sticking to the inside of blood vessels, brain blood flow was returned to normal, and performance on memory tests also improved. There is a type of cellular stress that is increased in Alzheimer's disease that could initiate the pathway that leads to the adherence of these immune cells in the blood vessels. We hypothesize that there are two types of cells at the root of this problem: One cell found in close proximity to blood vessels that might be responsible for generating too much of this cellular stress, and another cell that lines the inside of blood vessels that is responding to it. We aim to investigate the role of this cellular stress in reducing brain blood flow by targeting molecular pathways in the brain that will remove this cellular stress and bolster the brain's defences against cellular stress, in hopes of restoring blood flow, and memory. We will use experimental methods that target our two cell types of interest so that we can change how the cells respond to certain molecules by adding or removing certain genes to test our hypothesis. We will also deliver drugs to these cells specifically and examine their effects on cellular stress, brain blood flow, and memory. The proposed project seeks to increase our understanding of how cellular stress can lead to immune cell adhesion in brain blood vessels, and thus reduced brain blood flow. Our work will allow us to identify more cell-specific molecular targets for future drug development efforts with reduced drug side effects, aimed at interfering with immune cell adhesion to blood vessels.