Dena Dubal, M.D., Ph.D. University of California, San Francisco
Lee Rubin, Ph.D. Harvard University
Scott Small, M.D. Columbia University
Saul Villeda, Ph.D. University of California, San Francisco
Tony Wyss-Coray, Ph.D. Stanford University
Cognitive function declines with age, reflecting a complex and interrelated set of changes in neurons, neural stem cells, glia and vascular cells. This complexity presents a formidable challenge to neuroscientists studying the aging brain. However, a series of surprising observations has provided an exciting path forward. We have discovered that blood contains proteins that can restore some age-related cognitive decline. For example, giving old mice factors found in young blood can enhance the birth of new neurons, which typically slows with age. Blood proteins from younger animals can also restore declining blood vessel function in older animals, improving blood flow and the delivery of key nutrients to brain cells.
We have identified several different components in blood that have this effect, each of which appears to act differently. Certain factors appear to cross the blood-brain barrier and bind directly to receptors on neural and glial cells. Other factors may act on vascular cells, boosting neural function via better blood flow or by increasing the vascular system’s secretion of neuroactive factors.
We will investigate the blood-brain connection in several ways. First, we will use a novel labeling method, together with proteomics and RNA sequencing, to identify candidate blood proteins that can enter the brain and bind to receptors on neurons and glial cells. Second, we will use RNA sequencing and high-resolution imaging to determine how factors that don’t enter the brain restore blood vessel function. Finally, we will use molecular and behavioral assays to determine how selected factors exert their effects on neural function and improve cognitive performance. Our program should provide significant insight into the unexpected ability of blood factors to target the central nervous system.