Abstract

Construction of Human 3D Brain Model of Alzheimer’s Disease and Study of Microglial Inflammatory Activity Leading to Neuronal Damage

Hansang Cho, Assistant Professor, University of North Carolina-Charlotte

Alzheimer’s disease (AD) is characterized by amyloid beta (A-beta) and tau pathologies, which lead to cognitive impairment and memory deficits followed by neuronal loss. The underlying mechanisms of AD remain poorly understood in the absence of relevant human AD brain models. Here, we developed a new organotypic human AD brain model using a 3D microfluidic platform. This 3D AD brain microfluidic platform allows investigations of neuron-glia interactions by differentiating neurons and astrocytes from genetically modified human neural progenitor cells and co-culturing adult human microglia. In this model, AD brain signatures were observed with pathological levels of A-beta, phosphorylated tau, and tau tangles derived from neurons, and interferon-gamma (IFN-?) produced by astrocytes. Also, we validated microglial inflammatory activation: recruitment in response to co-cultured AD neurons, morphological changes, and release of pro-inflammatory cytokines. Notably, microglial activation induced by a combination of A-beta and IFN-?, led to neuronal loss mediated by microglial inducible nitric oxide synthase (iNOS) expression and NO release. These results suggest that our microfluidic human 3D AD brain model may prove useful in developing new treatments to limit neuronal loss.