A 3D Human Tri-Culture System Modeling Neurodegeneration and Neuroinflammation in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by beta-amyloid (Aβ) accumulation, phosphorylated tau (p-tau) formation, hyper-activation of glial cells, and neuronal loss. The mechanisms of AD pathogenesis, however, remain poorly understood partially due to the lack of relevant human models that can comprehensively recapitulate multistage-intercellular interactions in human AD brains. Here, we present a new 3D human AD tri-culture model by using neurons, astrocytes, and microglia in a 3D microfluidic platform (3D hNeuroGliAD). Our model provided key representative AD features: Aβ aggregation, p-tau accumulation and neuroinflammatory activity. In particular, the model mirrored microglial recruitment, neurotoxic activities such as axonal cleavage and NO release damaging AD neurons and astrocytes. Our model will serve to facilitate the development of more precise human brain models for basic mechanistic studies in neural-glial interactions and drug discovery.