ERI: Engineering perivascular microphysiological systems to discover hydrodynamic signatures of neurodegeneration

About This Grant

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 independent control of dual chamber flow to recreate, for the first time, the spectrum of perivascular flow conditions observed in the living brain. This ranges from healthy steady flows to pathological high-pulsatility conditions associated with aging and hypertension. Initially the project will quantify the aggregation kinetics of Amyloid-β-40 (a waste protein implicated in neurodegenerative disease) under physiologically relevant steady and pulsatile flow conditions. Using fluorescence-based assays and established kinetic modeling, rate constants for nucleation, elongation, and fibril fragmentation will be extracted and correlated with hydraulic power dissipation to capture energy available for protein misfolding. Next, human brain vascular smooth muscle cells and endothelial cells will be co-cultured within the platform to investigate flow-induced phenotypic switching. The project will determine whether pathological pulsatile flow activates specific mechanotransduction pathways that cause cells to transition from a healthy, contractile state to a dysfunctional, pro-inflammatory phenotype with reduced waste clearance capacity. Success will establish a quantitative framework linking CSF flow mechanics to the dual pathogenic mechanisms of protein aggregation and cellular dysfunction, revealing novel therapeutic targets that restore healthy brain fluid dynamics rather than biochemical pathways alone. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.