Engineering blood–brain barrier microphysiological systems to model Alzheimer's disease monocyte penetration and infiltration

Alzheimer's disease (AD) is a progressive and neurodegenerative disease, predominantly causing dementia. Despite increasing clinical evidence suggesting the involvement of peripheral immune cells such as monocytes in AD pathology, the dynamic penetration and infiltration of monocytes crossing blood-brain barrier (BBB) and inducing neuroinflammation is largely understudied in an AD brain. Herein, we engineer BBB-like microphysiological system (BBB-MPS) models for recapitulating the dynamic penetration and infiltration of monocytes in an AD patient's brain. Each BBB-MPS model can be engineered by integrating a functional BBB-like structure on a human cortical organoid using a 3D-printed device within a well of a plate. By coculturing these BBB-MPS models with monocytes from AD patients and age-matched healthy donors, we found that AD monocytes exhibit significantly greater BBB penetration and brain infiltration compared to age-matched control monocytes. Moreover, we also tested the interventions including Minocycline and Bindarit, and found they can effectively inhibit AD monocyte infiltration, subsequently reducing neuroinflammation and neuronal apoptosis. We believe these scalable and user-friendly BBB-MPS models may hold promising potential in modeling and advancing therapeutics for neurodegenerative and neuroinflammatory diseases.