Control of CSF hydrodynamics and brain-waste clearance

About This Grant

ABSTRACT: The accumulation of waste and neurotoxic proteins, such as amyloid-β and tau, is a hallmark of aging and neurodegenerative disorders like Alzheimer’s disease. The glymphatic system plays a critical role in brain-waste clearance. It facilitates the perfusion of cerebrospinal fluid (CSF) into the brain, which interchanges with interstitial fluid to flush out harmful waste, nanoplastics, and neurotoxic proteins. Our recent findings indicate that conditions impeding CSF flow dynamics—such as craniosynostosis and normal aging—disrupt this clearance system, exacerbating amyloid plaque buildup. Importantly, we have also shown that pharmacological activation of Piezo1, a mechanosensitive ion channel, using Yoda1 agonist enhances CSF-mediated waste clearance in both craniosynostosis and aged wild-type mice. However, a major gap remains in our understanding of how waste clearance is regulated at the cellular level. This obscures the cellular mechanism(s) by which Piezo1 acts to control brain waste clearance. Key preliminary data suggest that mechanical forces exerted by CSF flow may activate Piezo1 in brain border macrophages (BBMs). These cells are essential for brain waste clearance as they degrade extracellular matrix (ECM) proteins along arterial basement membranes, enabling proper arterial motion to drive CSF flow. This proposal aims to determine whether Piezo1 functions in BBMs to control brain-waste clearance, leveraging our team’s expertise in mouse genetics, high-resolution multi-photon imaging, and computational modeling. Aim 1 uses a pharmacological approach to investigate whether Yoda1 enhances brain-CSF perfusion by acting on BBMs to help regulate ECM remodeling. Aim 2 uses genetic approaches to directly test whether Piezo1 is required in BBMs to maintain CSF hydrodynamics and waste clearance by facilitating ECM degradation and arterial motion. Aim 3 examines the impact of Piezo1 manipulation in BBMs on amyloid pathology in mouse models of Alzheimer’s disease, including assessing whether stimulating Piezo1 activation can enhance amyloid clearance. By defining the role of Piezo1 in CSF- driven waste clearance, this work will establish a mechanistic framework for preserving glymphatic function across the lifespan. Targeting Piezo1 in BBMs may represent a novel therapeutic strategy to counteract age- related and disease-associated declines in brain-waste clearance, addressing a critical unmet need in Alzheimer’s disease and related dementias. As such, we expect our findings will lay the groundwork for translational efforts to develop new therapies aimed at sustaining cognitive health in aging populations. Our approaches may also be leveraged in the future to investigate how environmental pollutants (e.g., nanoplastic accumulation) may affect waste clearance and BBM functions, leading to cognitive impairment.