2023 Alzheimer’s Association Leveraging Model & Data Resources to Advance Alzheimer’s and Dementia Discovery Program (ALZDISCOVERY)
Understanding the Vascular Dysfunctions in MODEL-AD Mouse Models
What structural and genetic changes are involved in dementia-related brain blood vessel dysfunction?
Zhen Zhao, Ph.D.
University of Southern California
Los Angeles, CA - United States
Background
Studies show that loss of brain blood vessel (cerebrovascular) function may represent an early change in Alzheimer’s. This change, which can lead to nerve cell damage and death, often coincides with damage to a specialized structure called the blood brain barrier (BBB). The BBB helps maintain a healthy brain environment by tightly regulating what goes in and out of the brain from the circulating blood. For example, the BBB helps keep such harmful proteins as Alzheimer’s-related beta-amyloid and tau out of the brain. Loss of BBB function can promote beta-amyloid and tau accumulation in the brain, another change linked to brain cell damage and death in Alzheimer’s.
In recent years, scientists have focused on studying the genetic factors that underlie Alzheimer’s-related BBB and brain blood vessel damage. Such work involves analyzing the transcriptomes (or the complete sets of genes turned “on” at a specific time) in different brain cell types.
Research Plan
Dr. Zhen Zhao and colleagues will study BBB and cerebrovascular dysfunction in mice genetically engineered to develop various Alzheimer’s-like brain changes. First, they will identify structural changes that take place in the BBB and various brain blood vessels in these animals. They will also examine how such changes impact blood flow and other cerebrovascular functions. Next, they will use cutting-edge technologies to analyze the transcriptomes of thousands of cells in the animals’ brains. This work will enable them to construct a “map” of genetic changes that take place in the brain, and indicate which cells and which brain regions may be most susceptible to dementia-related vascular and BBB damage.
Impact
The results of Dr. Zhao’s project will refine our understanding of how vascular dysfunction impacts brain health and promotes dementia. They could also lead to novel genetic therapies that target vascular and BBB changes.