Incurable brain diseases, including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), are caused by an unhealthy buildup of normal brain waste proteins. Recent research has shown that the brain uses cerebrospinal fluid (CSF), a clear fluid that surrounds and cushions the brain, to flush out these wastes. Waste proteins often build up around arteries, where the fluid pulses with each heartbeat, but not around veins, where the flow is steady. This pattern is puzzling, because "clean" fluid enters near arteries while “dirty” waste-laden fluid empties near veins. This Engineering Research Initiation (ERI) project tests the hypothesis that pulsing flow, which becomes more vigorous with age and disease, may explain this pattern in two ways. First, since flowing fluid puts physical forces on protein molecules, it can change how they fold and clump together, similar to plaque formation in heart disease. Second, cells lining these tunnels may respond to these vigorous fluid forces and become depots of waste deposition. The project will test these ideas by building a device that mimics the brain’s fluid and cellular environments, while enabling precise control over flow patterns. The device will measure how proteins clump under different CSF flows and how cells respond to these fluid forces. Understanding how disease-associated flow patterns may cause waste buildup will guide new treatments for brain disease that target restoration of healthy flow. The project will train graduate and undergraduate students in biotechnology research and engage high school students through hands-on bioengineering demonstrations. This ERI project will develop a novel microphysiological system to systematically investigate how CSF hydrodynamics influences diseases like Alzheimer’s through two complementary mechanisms: flow-induced protein aggregation and cellular mechanotransduction. Using a validated silicon-nitride membrane tissue-chip platform, the system will enable inde