Abstract
The driving mechanisms at the base of the clearance of biological wastes in the brain interstitial space (ISS) are still poorly understood and an actively debated subject. A complete comprehension of the processes that lead to the aggregation of amyloid proteins in such environment, hallmark of the onset and progression of Alzheimer's disease, is of crucial relevance. Here we employ combined computational fluid dynamics and molecular dynamics techniques to uncover the role of fluid flow and proteins transport in the brain ISS. Our work identifies diffusion as the principal mechanism for amyloid-β proteins clearance, whereas fluid advection may lead transport for larger molecular bodies, like amyloid-β aggregates or extracellular vesicles. We also clearly quantify the impact of large nascent prefibrils on the fluid flowing and shearing. Finally, we show that, even in the irregular brain interstitial space (ISS), hydrodynamic interactions enhance amyloid-β aggregation at all stages of the aggregation pathway. Our results are key to understand the role of fluid flow and solvent-solute interplay on therapeutics like antibodies acting in the brain ISS.