Understanding the Role of Cerebral Vasculature AD Pathology Using a Knock-in Mouse Model with CAA

Project Summary

The first aim of is to identify whether abnormal changes in cerebral (brain) blood flow can aggravate and promote AD. Surgical procedures on the left carotid artery (one of the two large vessels that pass by the voice box in the neck) can differentially change the blood flow on the left and right side of the brain in the mouse model of AD. This provides a tool to study how abnormal blood flow in the brain affects amyloid formation and beta-amyloid (Abeta) clearance. Next, Dr. Li will search for treatments that can protect blood vessels and investigate whether they can prevent, halt, or reverse the progress of AD in an age-dependent fashion in the mouse model.

Dr. Li has already engineered the novel AD mouse model of Familiar AD, where the mice have mutations in their APP and PS1 genes, and express a human form of Abeta. This mouse model is more similar to the true nature of the human disease, and thus offers a distinct advantage for mechanistic studies as compared to other mouse models. These mice exhibit age-dependent symptoms, including reduced brain blood flow, prominent Abeta deposit around blood vessels (a process called cerebral amyloid angiopathy, or CAA) and Abeta brain plaques, as well as cognitive deficits, which reflect many of the key symptoms of AD patients.

Upon completion of these studies, Dr. Li is hoping to gain more insights on how the health of blood vessels and the resulting changes in the cerebral blood flow influences the development and progression of AD. Furthermore, since the mouse model is more disease relevant and suitable for mechanistic studies, she is hoping that successful therapies identified with these mice will not only provide a better understanding of the disease, but also can lend ideas to future human clinical trials.