Image: blood vessels in the brain
by Sarah Baker, Graduate Fellow, Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY
Field of Research: Neuroscience
Proteins carry out virtually all of the biochemical processes within the body. Each protein must be folded into a precise three-dimensional shape in order to carry out its proper function, and when this precise folding fails to happen, this can lead to drastic negative consequences to human health. Many different diseases are characterized by faulty proteins that have gained an incorrect shape, causing them to become “sticky” and clump together, and these diseases are classified as amyloid diseases. One well known amyloid disease is Alzheimer’s disease, a disorder characterized by protein build-ups in the brain which lead to the death of brain cells and, consequently, memory loss and other cognitive deficits.
Alzheimer’s disease does not become diagnosable until patients start to show signs of memory loss, but there is increasing evidence that this disease may begin much sooner in life as a result dysfunction of the vascular system. This is what I study: how the vascular system is linked with proper brain functioning in Alzheimer’s disease. The brain has high energy needs and is critically reliant on sufficient blood flow to carry out its processes. The fact that cardiovascular health risk factors such as stroke, blood pressure, high cholesterol, and obesity are also risk factors for Alzheimer’s disease suggests that this disease may also be driven by vascular mechanisms originating in the blood. In addition, Alzheimer’s patients often have increased blood clotting as well as chronic inflammation.
I am interested in studying how inflammation that starts in the blood can lead to brain inflammation characteristic of Alzheimer’s disease. In order to study this question, I have depleted plasminogen, a protein that plays a role in breaking down blood clots and increasing inflammation, in the blood of an Alzheimer’s disease mouse model. This model expresses genetic mutations that are known to be associated with early onset forms of Alzheimer’s disease, and these mice show amyloid plaque deposition, inflammation, and memory deficits by 3-4 months of age. I have shown that depleting plasminogen decreases inflammation in the brain, leads to less deposition of amyloid protein in the brain, and increases cognition and memory in behavioral tests.
In this image, we are looking at activation of microglia, the resident immune cells of the brain. More microglial activation corresponds to higher levels of inflammation. There is a high degree of microglial activation in the Alzheimer’s mouse brain when these mice have normal levels of plasminogen in the blood. However, when plasminogen is depleted in the blood, they show brain levels of inflammation comparable to that seen in non-Alzheimer’s mice, suggesting that vascular-derived plasminogen may contribute to brain pathology in this disease. This suggests that depleting important inflammatory mediators in the blood, such as plasminogen, may be a potential therapeutic for Alzheimer’s disease and other diseases with high levels of inflammation in the brain.
Because we still do not understand a mechanism by which vascular plasminogen affects brain inflammation, I am continuing to study how this blood protein is affecting the brain and contributing to the pathology of Alzheimer’s disease. Specifically, I would like to understand how plasminogen in the blood contributes to inflammation there and furthermore how it can signal to increase inflammation in the brain as well.