Objective:

Unravelaing mechanisms underlying Alzheimer’s disease (AD) 

Background:

A growing body of evidence supports the idea that neurovascular unit (NVU) dysfunction and blood-brain barrier (BBB) breakdown are major contributors for AD development. However, the mechanism underlying NVU dysfunction contributing to AD is still not fully understood.

Design/Methods:

A three-dimensional in vitro NVU model was used as a compartmentalized microfluidic device. It contains five cell types in a dynamic and tunable microenvironment, resulting in an in vivo-like response. Each chip contains two fluidic compartments separated by a porous membrane. The vascular compartment is lined with endothelial cells (EC), while the brain compartment contains cortical neurons, astrocytes, pericytes, and microglia. Cultured cells on both sides of the porous membrane, provided cell-cell interactions resembling in-vivo microenvironment. We evaluated the toxic effects of Amyloid β oligomers (Aβo) and Tau oligomers (TauO) by adding both to the brain compartment and adding only Aβo to the vascular compartment. Twenty-four hours after the treatment, indicators of permeability were measured using Dextran 3 kDa, and occluding levels.

Results:

After 24 hours of treatment, our preliminary data showed that Aβo and TauO produce cytotoxicity as indicated by an increased permeability, compared to the control chips. This toxic effect was supported by a significant increase in the crossing of Cascade Blue 3KDa between the compartments, as an indicator of increasing permeability, as well as a decrease in occludin levels. As the concentration of Aβo increased, a corresponding rise in permeability was observed.

Conclusions:

This is a human-based in vitro model that offers dynamic cell-cell interactions to investigate BBB function continuously with and without Aβo and TauO as well as discover therapeutic target capabilities. Our preliminary results suggest that Aβo and TauO provoke vascular cytotoxicity, BBB dysfunction and increased permeability. These data together suggest that NVU-on-a-chip is a good model for testing NVU dysfunction in AD