What question did this study set out to answer?

The aim is to create a model that closely mimics the complex interactions in Alzheimer's disease to better understand neurovascular dysfunction.

March 5, 2026Molecular Brain0 citationsOpen Access

Recapitulating Alzheimer’s disease pathophysiology with a microfluidic neurospheroid-grafted endothelial barrier model

SUSamuel C. Uzoechi CCC. Dean Campbell CBCody Joseph Badeaux

Puntos clave

The aim is to create a model that closely mimics the complex interactions in Alzheimer's disease to better understand neurovascular dysfunction.
Developed a microfluidic endothelial barrier integrated with familial Alzheimer's disease neurospheroids.
Cultured human endothelial cells in perfusable channels to mimic a vascular-like environment.
Grafted pre-differentiated neurospheroids into the brain chamber.
Assessed barrier integrity, tight-junction expression, and amyloid-beta production using immunofluorescence imaging and ELISA.
The model showed increased endothelial permeability and reduced ZO-1 expression compared to controls.
Elevated levels of phosphorylated tau (pTau) were observed in the neurospheroid-grafted construct.
Endogenous amyloid-beta production and selective distribution were documented, consistent with Alzheimer's disease pathology.
Notable alterations in neuronal and endothelial functions were evident within this integrated 3D system.

Resumen

Abstract Background Traditional two-dimensional (2D) models do not adequately capture the complex cellular interactions, brain-specific architecture, and progressive pathology of Alzheimer’s disease (AD). Three-dimensional (3D) organoid and microfluidic technologies provide more physiologically relevant platforms for studying AD-associated neurovascular dysfunction. Methods We developed a membrane-free microfluidic endothelial barrier model integrated with neurospheroids derived from familial AD (FAD) neural progenitor cells. Human endothelial cells were cultured within perfusable microfluidic channels to establish a vascular-like interface rather than a fully specialized BBB endothelium. Pre-differentiated neurospheroids were grafted into the brain chamber. Endothelial barrier integrity, tight-junction expression, phosphorylated tau (pTau), and Aβ42/Aβ40 production and distribution between compartments were assessed using immunofluorescence imaging and ELISA. Results The neurospheroid-grafted endothelial barrier construct captured key AD-associated phenotypes. ReN-AD-D4 models exhibited increased endothelial barrier permeability, reduced ZO-1 expression, and elevated pTau relative to controls. The platform supported endogenous Aβ generation, accumulation, and endothelial-associated deposition at the endothelial barrier. ELISA demonstrated differential Aβ42 and Aβ40 distribution, consistent with isoform-selective behavior reported in AD pathology. Collectively, these results indicate co-occurring neuronal and endothelial barrier alterations within the integrated 3D system. Conclusion This microfluidic endothelial barrier–neurospheroid platform enables quantitative assessment of amyloid-β accumulation, spatial distribution, and compartmentalized secretion alongside tau pathology and endothelial barrier integrity changes. Integrating human endothelial monolayers with FAD-derived neurospheroids, the system is scalable and compatible with high-content imaging. Although it does not model BBB-specific transport mechanisms, it provides a robust framework for hypothesis-driven studies of neurovascular interactions and therapeutic screening applications.

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