INVESTIGATING THE ROLE OF PERICYTES IN ALZHEIMER’S DISEASE DRUG DELIVERY USING IPSC-DERIVED BBB MODELS AND FOCUSED ULTRASOUND

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which effective disease-modifying therapies remain limited, in part due to restricted drug delivery across the blood–brain barrier (BBB). Focused ultrasound (FUS) combined with microbubbles has emerged as a promising non-invasive strategy to transiently increase BBB permeability. Using human iPSC-derived brain endothelial-like cells (iBECs), we have previously shown that FUS enhances the permeability of therapeutic agents across an in vitro BBB model, supporting its potential application for AD drug delivery.
Despite these advances, the contribution of pericytes, essential components of the neurovascular unit and key regulators of BBB integrity, remains poorly understood in the context of FUS-mediated BBB opening. To address this gap, we established a human iPSC-derived co-culture BBB model incorporating iBECs and pericytes in a transwell system. Preliminary results indicate that co-culture with pericytes significantly alters BBB integrity compared to iBEC monocultures, suggesting a modulatory role of pericytes on endothelial barrier properties and baseline permeability.
Building on these findings, we aim to investigate how pericytes influence BBB responses to FUS and whether FUS-induced permeability differs between iBEC-only models and iBEC–pericyte co-cultures. We will further assess how pericytes modulate therapeutic transport following FUS, providing mechanistic insight into cell–cell interactions that govern BBB function. This project will advance our understanding of pericyte-mediated regulation of the human BBB, a critical yet underexplored aspect of AD pathophysiology.