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How can certain blood vessel cells promote blood vessel dysfunction and beta-amyloid clumping in brain disease?
Praveen Bathini, Ph.D.
Brigham and Women's Hospital
Boston, MA - United States
Background
Adequate blood flow is essential for delivering oxygen and nutrients needed to maintain brain function. Increasing evidence suggests that damage to the brain’s blood vessels may increase the risk of developing Alzheimer’s and related dementias. Reductions in blood flow could be connected to the build-up of beta-amyloid in the blood vessels – a condition known as cerebral amyloid angiopathy (CAA). Beta-amyloid is the protein fragment that can form plaques in the brain tissue, a hallmark of Alzheimer’s.
One way that CAA may impact brain blood flow is through the blood-brain barrier (BBB), a specialized structure that helps maintain a healthy brain environment by tightly regulating what goes into and out of the brain from the circulating blood. The BBB is composed of different cells that help clear toxic debris from the brain. These cells include pericytes, a specialized type of cell located in the walls of blood vessels. Pericytes work with other cells to keep the brain and BBB functioning, and they may also help clear beta-amyloid from the brain. Studies, however, have shown that pericyte function can become disrupted in Alzheimer’s, especially in pericyte cells with APOE-e4, a gene variation linked to increased Alzheimer’s risk in some populations. More research will be needed to better understand these disease processes.
Research Plan
Dr. Praveen Bathini and colleagues will conduct a study of pericytes in CAA and Alzheimer’s by first growing pericyte cells in a laboratory dish – cells that express either APOE-e4 or APOE-e3 (an APOE variation shown to maintain normal brain function). They will then add beta-amyloid onto the cells and examine how the different pericyte varieties clear beta-amyloid molecules. Next, they will genetically analyze the APOE-e4 and APOE-e3 pericytes after beta-amyloid treatment, in order to identify other genes that may be associated with beta-amyloid clearance. Lastly, the researchers will use genetically engineered mice that develop beta-amyloid plaques and also have reduced levels of APOE-e4 pericytes. They will then administer an antibody therapy to the mice that uses the body’s own immune system to lower amyloid production. After administering the treatment, Dr. Bathini’s team will assess how lowering APOE-e4 in pericytes may improve beta-amyloid clearance and reduce abnormal bleeding (a common side-effect of amyloid antibody treatment).
Impact
Results from this study could improve the understanding on the role of pericytes and APOE in brain disease. They could also lead to safer, more effective antibody therapies that prevent Alzheimer’s- or CAA-related amyloid build-up in humans.
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