2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)
How Do Meningeal Lymphatics Affect Cerebral Amyloid Angiopathy?
Could improving the brain’s clearance system prevent other biological changes associated with Alzheimer’s?
Fareeha Saadi, Ph.D.
Washington University in St.Louis
St Louis, MO - United States
Background
The brain uses a clearance mechanism to remove toxins and other things that may cause it harm. This “flushing” system links a series of fluid-filled channels or vessels to one another, known as the meningeal lymphatic system. This system connects the fluid that surrounds the brain to the fluid that surrounds the spinal cord (known as cerebrospinal fluid). This connection allows immune cells to enter as well as allowing unwanted or waste molecules to drain. Previous research has shown people with Alzheimer’s have less efficient “flushing” systems than cognitively healthy people. It may be that the disease affects their ability to effectively clear disease-related brain changes.
People with Alzheimer’s are at high risk for another disease called cerebral amyloid angiopathy (CAA). In CAA, brain changes can lead to stiffening of the vessels and problems with blood circulation. Recent studies have also found that in individuals with CAA, the fluid-filled spaces around blood vessels become enlarged, suggesting improper drainage from these spaces. The exact connections between impaired clearance systems and CAA in Alzheimer’s are not yet clear.
Research Plan
Dr. Fareeha Saadi and colleagues are studying how problems with meningeal lymphatic function might increase risk of CAA. To investigate this, the research team will study mice that have been genetically engineered to lack the vessel connections. The researchers will analyze cells found in blood vessel and brain tissue samples collected from the mice for immune cells and measure specific changes in the surrounding fluid. They will also look for signs of CAA in the brain tissue samples. The researchers will compare their results to those with healthy lymphatic systems. This will help grow understanding of how an impaired lymphatic system may influence disease-related changes.
In a second part of the study, Dr. Saadi will study ways to improve fluid flow in the lymphatic system using another model that has been genetically engineered to have wider vessels. Dr. Saadi believes wider vessels may help improve clearance of toxins that may contribute to the disease. The researchers will perform similar analyses as in the first part of the study and determine if enhancing the function of lymphatic systems reduces the risk of developing biological changes associated with CAA.
Impact
This study could determine whether the vessels that comprise the meningeal lymphatic system might be future therapeutic targets for drugs designed to delay, or even prevent CAA. The study might also uncover ways to enhance beta-amyloid clearance from the brain or cerebrospinal fluid in Alzheimer’s.