Q & A - Oliver Bracko & Nancy Ruiz
To understand neurodegenerative diseases, why is it important to investigate brain blood flow? Is there a link between brain blood flow and dementia? [Oliver] In your published Nature Neuroscience study, how did your team at Cornell University use mice to study the role of brain blood flow in Alzheimer’s diseases? [Oliver]
We have known for decades that blood flow to the brain is reduced up to one-third in patients with Alzheimer ’s disease. This is a large reduction in blood flow, similar in size to the brain blood flow decrease that causes the transient dizziness sometimes experienced when standing up too quickly after lying down. In Alzheimer ’s, large brain blood flow reductions are likely contributing to the memory and cognitive problems, but we don’t yet fully understand the mechanistic connection and studies aiming to understand the mechanism behind these reductions are just beginning. Most likely several mechanisms are in play, and lifestyle factors such as cardiovascular risk factors, like obesity or Type2-diabetes, have an impact. Furthermore, genetic risk factors such as APOE4, the largest genetic risk factor known to be associated with Alzheimer ’s, are directly or indirectly contributing to the overall brain blood flow reduction seen in patients. Recently several clinical trials have failed, which aimed to reduce the pathological hallmarks of Alzheimer ’s amyloidbeta plaques as well as hyperphosphorylated tau. It becomes more evident that alternatives to such treatments are in great need. Understanding brain blood flow reductions and their contributions to Alzheimer ’s disease is an important prerequisite to develop novel treatment strategies.
We are an engineering lab and develop microscopes. Our technology enabled us to study capillary blood flow in mice genetically engineered to develop Alzheimer ’s. Although it is possible to study overall blood flow in human patients with methods like MRI, it is impossible to resolve the blood flow of the smallest vessels (capillaries) of the brain. In mice, we identified that brain blood flow decrease is caused by white blood cells (leucocytes) stuck to the inside of the capillaries in the brain. Because blood cells flow in a single file in capillaries, the adhered white blood cells transiently block blood flow in these vessels. While only a couple percent of capillaries have stalled blood flow due to these blockages, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow. When we used an antibody that blocks leucocytes’ adhesion, the stalled capillaries started flowing again, and brain blood flow speed quickly increased by about 20%. When we tested the impact of improved brain blood flow on mice performance on memory tasks, we found that memory function was improved within hours of giving the antibody that interfered with white blood cell adhesion.
Directly below: Oliver at a two-photon microscope.
Below, left: Vascular inflammation imaging blood is red inflammation blue and green. Both images: © Oliver Bracko. All rights reserved.
With your citizen science project Stall Catchers, how are you speeding up Alzheimer’s research? Have the participants shared their experiences taking part? [Nancy]
Stall catchers has been a great tool for us because we have been able to engage a lot of people (scientists and non-scientists) with the research that we do in the lab and they also help us analyze our data, which takes a long time for us to do just by ourselves.
“...exercise is beneficialfor cognitive function, and should play an active role in therapies against Alzheimer’s disease.”
I have seen a lot of enthusiasm from participants, especially elder people who like to help with speeding up Alzheimer ’s research, because it feels personal to them. Playing the game also represents a way in which they can stimulate their brain by using their phones or personal laptops.
Which insights from your research aid the future development of Alzheimer’s therapies? Why may exercise be beneficial for patients, according to your recently published PLOS One pilot study? [Nancy]
In our pilot study, even though we did not find any changes in cerebral blood flow or capillary stalls, we found an increase in neurogenesis in the dentate gyrus (new neurons being formed in a region in the hippocampus that is crucial for memory) and an improvement in cognitive function, specifically in short term memory tasks, after only three months of voluntary running in mouse models of the disease.
This, along with many other studies of exercise and its effect on Alzheimer ’s disease, proves that exercise is beneficial for cognitive function, and that exercise should play an active role in therapies against the disease.