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2017 Grants - Hefendehl
The Role of Pericytes in Alzheimer's Disease and Stroke Comorbidity
Jamin Hefendehl, Ph.D.
2017 Alzheimer's Association Research Fellowship (AARF)
How does damage to blood vessels in the brain contribute to Alzheimer's disease?
It is increasingly clear that damage to blood vessels in the brain is an important contributor to the development of dementia, such as Alzheimer's disease. Loss of blood flow to the brain or the breakdown of the protective barrier between the blood and brain can damage nerve cells and impair memory and learning, leading to vascular cognitive impairment (VCI). Many individuals with Alzheimer's disease also have evidence of VCI in the brain. Specifically, the activity of pericytes, a specialized type of cell located in the walls of blood vessels, are altered in the brains of individuals with Alzheimer's disease and VCI.
In Alzheimer's disease research, mice genetically engineered to develop an Alzheimer's disease-like condition have been critical to understanding the progression of changes that occur in the brain and the effect these changes have on learning and memory. However, there is a need for a mouse model that develops the characteristics of both Alzheimer's disease—accumulation of the protein fragment beta-amyloid and the protein tau, which interfere with nerve cell function in the brain—and VCI. Such a mouse model would more closely represent the progression of Alzheimer's disease in humans.
Jasmin Hefendehl, Ph.D., and colleagues developed a new, genetically engineered mouse that shows tau accumulation and nerve cell loss (hallmarks of Alzheimer's disease) and degeneration of pericytes (hallmark of VCI). Using this new mouse model, they found that pericytes are essential for repairing "leaky" blood vessels and stimulating the growth of new blood vessels in the brain.
Dr. Hefendehl and colleagues now propose to develop a series of additional mouse models to better understand the relationship between changes in the brain related to Alzheimer's disease (accumulation of beta-amyloid) and changes that damage pericytes in the blood vessels of the brain, similar to what occurs in VCI. They will investigate the timing of changes that occur and how the accumulation of beta-amyloid impairs the ability of pericytes to repair damaged blood vessels and stimulate new blood vessel growth. They will also determine whether molecules that are released when blood vessels in the brain are damaged cause further damage to the pericytes and nerve cells.
This study may help determine how changes in the nerve cells and the blood vessels in the brain both contribute to the development of Alzheimer's disease. It may lead to the development of new therapies that address both processes to slow the progression of the disease.