Numerical simulations reveal complementary function of blood-brain barrier and glymphatic transport in the brain

The brain's high metabolic activity generates protein waste that must be efficiently cleared to avoid the formation of toxic aggregates associated with neurodegenerative diseases such as Alzheimer's (AD). Two primary pathways facilitate this clearance: the blood-brain barrier (BBB) and the glymphatic system. In the latter pathway, cerebrospinal fluid (CSF) flows through perivascular spaces (PVSs) - annular channels around the vessels in the brain - and mixes with interstitial fluid to aid in waste removal through bulk flow. The BBB comprises active transporters on the vasculature walls that permit waste proteins to cross from the brain into the blood. Despite their importance, the interplay and complementary roles of these two pathways are not well understood. To address this, we developed a Lattice Boltzmann simulation to model the clearance of amyloid-β (Aβ), a peptide associated with AD, from the brain tissue. This model includes arteries, veins, capillaries, and both clearance routes. We calibrated our model by activating different pathways and comparing the results with available experimental data of selectively deactivated Aβ production and/or BBB efflux. The results allowed us to derive critical parameters not yet measured in experiments and revealed distinct, complementary roles of the two waste clearance routes. Our study underscores the generic nature of these dual pathways in transporting large molecules, and our approach can be adapted to probe other proteins or drug delivery to the brain.