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2013 Grants - Yao
Novel Mechanisms of BACE1 in Alzheimer's Vascular Pathogenesis
Hailan Yao, Ph.D.
Roskamp Foundation IRRV Trust
2013 New Investigator Research Grant
Cardiovascular problems, including high blood pressure and stroke, are important risk factors for Alzheimer's disease and other dementias. Moreover, damage to the brain's blood vessels can exacerbate the abnormal brain changes and behavioral symptoms of dementia. The protein fragment beta-amyloid, a key suspect in Alzheimer's, may accumulate in and around blood vessels of the brain. This pathology is called cerebral amyloid angiography (CAA), and it damages the vessel walls and leads to bleeding in the brain and possible declines in memory and other forms of cognition. Yet the biological mechanisms underlying CAA are poorly understood.
In preliminary research, Hailan Yao, Ph.D., and colleagues identified a particular aspect of CAA that may contribute to Alzheimer's disease changes in the brain, or pathology. This aspect involves damage to endothelial cells, the specialized cells lining blood vessel walls in the brain. During Alzheimer's disease, proteins called caspases—which are normally involved in cellular communication and metabolism—become overly activated. Caspase activation, in turn, can overstimulate another protein called BACE1. BACE1 is one of several enzymes that "clip" beta-amyloid, a protein fragment linked to Alzheimer's disease, from its longer parent molecule. Elevated caspase and BACE1 activity may initiate the endothelial cell damage that leads to CAA, which in turn causes cognitive decline. Dr. Yao and colleagues will test this hypothesis using cultured brain cells and mice engineered to develop both CAA and Alzheimer's-like symptoms. The results of their effort could shed new light on how blood vessel damage and brain dysfunction are linked.